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To evaluate the association between C-reactive protein (CRP) and 10-year risk of cardiovascular (CV) events using the Expanded Cardiovascular Risk Prediction Score for Rheumatoid Arthritis (ERS-RA), based on conventional and RA-specific risk factors but not CRP, in RA patients without previous cardiovascular events.ERS-RA was calculated in 1,251 "Cardiovascular Obesity and Rheumatic Disease Study (CORDIS)" database patients [(age 60.4(9.3) years; 78% female; disease duration, 11.6(8) years; CDAI, 9(9); CRP, 6.8(12) mg/L].The mean (SD) 10-year risk of CV events was 12.9% (10). After adjusting for the use of DMARDs and biologics, CRP concentrations were significantly associated with 10-year risk of CV events (coefficient=0.005 for each 10 mg/L CRP increment; 95%CI 0.000-0.111; p = 0.047). In mediation analysis, the association between CRP and ERS-RA was not explained by disease activity.In a large cohort of RA patients without previous cardiovascular events, a 20 mg/L increase in CRP concentrations was associated with a 1% increase in 10-year risk of CV events. This suggests that actively targeting residual inflammatory risk beyond conventional and RA-specific risk factors might further reduce CV event rates in RA patients.

Diabetes mellitus is associated with impairment in cognitive functions which can complicate adherence to self-care behaviors. We evaluated the incidence of cognitive impairment in patients with diabetes mellitus to determine the strength of the association between diabetic foot (a complication that occurs in about 10% of diabetic patients), adherence to the clinician&rsquo, s recommendations, glycemic control, and cognitive function. A prospective study was carried out in a probabilistic sample of older patients with diabetic foot living in three nursing homes. Cognitive functions were evaluated by the MMSE (Mini-Mental State Examination), the Trail Making test (TMT), and the Michigan neuropathy screening instrument (MNSI). There were no significant associations between cognitive function and neuropathy or foot alterations, although glycated hemoglobin (HB1Ac &gt, 7%) significantly (p &lt, 0.05) associated with MMSE and adherence to treatment in the 1 month follow-up visit. Receiver operating characteristic curve analysis showed that both HB1Ac and the MNSI score significantly (p &lt, 0.05) discriminate subsequent adherence to treatment for foot complication, with a sensitivity of 80.0&ndash, 73.3% and specificity 70.6&ndash, 64.7%, respectively. Proper control of foot complications in diabetic patients involves appropriate glycemic control and less severe neuropathy, and seems to be unrelated to cognitive dysfunction, and warrants further studies in order to tailor appropriate treatments to central and peripheral nervous system disorders. Poor glycemic control (Hb1Ac level &gt, 7%) and a neuropathy score of 5.5 in the MNSI are the best-cut off points to discriminate poor adherence to the clinician&rsquo, s recommendations for self-care behaviors in people with diabetic foot complication. In this study, we observed that foot disorders were associated with impaired global cognitive function in elderly patients (aged &ge, 65). Podiatrists and physicians should consider cognitive dysfunction as an important chronic complication in the management of diabetic foot.

Purpose of the present paper is to point out the design, development and deployment of the AutoInflammatory Disease Alliance (AIDA) International Registry dedicated to pediatric and adult patients with Behçet’s disease (BD). The Registry is a clinical physician-driven non-population- and electronic-based instrument implemented for the retrospective and prospective collection of real-life data about demographics, clinical, therapeutic, laboratory, instrumental and socioeconomic information from BD patients; the Registry is based on the Research Electronic Data Capture (REDCap) tool, which is thought to collect standardised information for clinical real-life research, and has been realised to change over time according to future scientific acquisitions and potentially communicate with other existing and future Registries dedicated to BD. Starting from January 31st, 2021, to February 7th, 2022, 110 centres from 23 countries in 4 continents have been involved. Fifty-four of these have already obtained the approval from their local Ethics Committees. Currently, the platform counts 290 users (111 Principal Investigators, 175 Site Investigators, 2 Lead Investigators, and 2 data managers). The Registry collects baseline and follow-up data using 5993 fields organised into 16 instruments, including patient’s demographics, history, clinical manifestations and symptoms, trigger/risk factors, therapies and healthcare access. The development of the AIDA International Registry for BD patients will facilitate the collection of standardised data leading to real-world evidence, enabling international multicentre collaborative research through data sharing, international consultation, dissemination of knowledge, inclusion of patients and families, and ultimately optimisation of scientific efforts and implementation of standardised care.Trial registration NCT05200715 in 21/01/2022.

Pharmacological therapy targeting the HER2 protein is one of the major breakthroughs in the treatment of cancer patients overexpressing HER2 who have increased survival rates. Despite improved survival, it is important to determine the less frequent adverse effects in order to tailor treatments more personalized to the patients’ features. The possible impact of cancer treatments on cognitive functions is huge, and the effects of anti-HER 2 therapies on this issue have not been reviewed and are the objective of this study. Analysis of PubMed, Scopus, Cochrane library and Web of Science databases revealed six studies performed in breast and serous uterine cancer patients analyzing cognitive function under chemotherapy regimens including anti-HER2 drugs. Four of these studies reported small to significant worsening of cognitive function following chemotherapy regimens containing trastuzumab (the most widely used anti-HER2 drug). In neoadjuvant settings, and in breast cancer patients, treatment with the new anti-HER-2 drug trastuzumab emtansine seems to induce less cognitive impairment than therapeutic regimens containing chemotherapy and trastuzumab. Acute administration of trastuzumab induced cognitive impairment in gastric cancer mice models, confirming its ability to alter cognitive function in patients. More studies analyzing the impact of anti-HER2 therapy on cognitive function are necessary at preclinical and clinical levels in order to personalize pharmacological treatment and offer cancer patients a better quality of life.

A systematic review and meta-analysis were conducted, according to the PRISMA methodology, to summarize current evidence on the prevalence and predictors of long-term glucocorticoid (GC) treatment and disease relapses in the real-life management of polymyalgia rheumatica (PMR).Out of 5442 retrieved studies, 21 were eligible for meta-analysis and 24 for qualitative analysis. The pooled proportions of patients still taking GCs at 1, 2, and 5 years were respectively 77% (95%CI 71–83%), 51% (95%CI 41–61%), and 25% (95CI% 15–36%). No significant difference was recorded by distinguishing study cohorts recruited before and after the issue of the international recommendations in 2010. The pooled proportion of patients experiencing at least one relapse at 1 year from treatment initiation was 43% (95%CI 29–56%). Female gender, acute-phase reactants levels, peripheral arthritis, starting GCs dosage, and tapering speed were the most frequently investigated potential predictors of prolonged GC treatment and relapse, but with inconsistent results. Only a few studies and with conflicting results evaluated the potential role of early treatment with methotrexate in reducing the GC exposure and the risk of relapse in PMR.This study showed that a high rate of prolonged GC treatment is still recorded in the management of PMR. The relapse rate, even remarkable, can only partially explain the long-term GC treatment, suggesting that other and not yet identified factors may be involved. Additional research is needed to profile patients with a higher risk of long-term GC treatment and relapse and identify more effective steroid-sparing strategies.Key Points:• High rate of long-term glucocorticoid (GC) treatment is recorded in polymyalgia rheumatica (PMR), being 77%, 51%, and 25% of patients still on GCs after respectively 1, 2, and 5 years.• A pooled relapse rate of 43% at 1 year, even remarkable, can only partially explain the long-term GC treatment in PMR.• Several studies have attempted to identify potential predictors of prolonged treatment with GCs and relapse, but with inconsistent results.• Additional research is needed to profile patients with a higher risk of long-term GC treatment and relapse and identify more effective steroid-sparing strategies.

Although cancer and diabetes are common diseases, the relationship between diabetes, neuropathy and the risk of developing peripheral sensory neuropathy while or after receiving chemotherapy is uncertain. In this review, we highlight the effects of chemotherapy on the onset or progression of neuropathy in diabetic patients. We searched the literature in Medline and Scopus, covering all entries until 31 January 2021. The inclusion and exclusion criteria were: (1) original article (2) full text published in English or Spanish; (3) neuropathy was specifically assessed (4) the authors separately analyzed the outcomes in diabetic patients. A total of 259 papers were retrieved. Finally, eight articles fulfilled the criteria, and four more articles were retrieved from the references of the selected articles. The analysis of the studies covered the information about neuropathy recorded in 768 cancer patients with diabetes and 5247 control cases (non-diabetic patients). The drugs investigated are chemotherapy drugs with high potential to induce neuropathy, such as platinum derivatives and taxanes, which are currently the mainstay of treatment of various cancers. The predisposing effect of co-morbid diabetes on chemotherapy-induced peripheral neuropathy depends on the type of symptoms and drug used, but manifest at any drug regimen dosage, although greater neuropathic signs are also observed at higher dosages in diabetic patients. The deleterious effects of chemotherapy on diabetic patients seem to last longer, since peripheral neuropathy persisted in a higher proportion of diabetic patients than non-diabetic patients for up to two years after treatment. Future studies investigating the risk of developing peripheral neuropathy in cancer patients with comorbid diabetes need to consider the duration of diabetes, cancer-induced neuropathic effects per se (prior chemotherapy administration), and the effects of previous cancer management strategies such as radiotherapy and surgery.

Objectives To investigate survival of IL-1 inhibitors in monogenic autoinflammatory disorders (mAID) through drug retention rate (DRR) and identify potential predictive factors of drug survival from a real-life perspective. Patients and methods Multicentre retrospective study analysing patients affected by the most common mAID treated with anakinra or canakinumab. Survival curves were analysed with the Kaplan-Meier method. Statistical analysis included a Cox-proportional hazard model to detect factors responsible for drug discontinuation. Results Seventy-eight patients for a total of 102 treatment regimens were enrolled. The mean treatment duration was 29.59 months. The estimated DRR of IL-1 inhibitors at 12, 24 and 48 months of follow-up was 75.8%, 69.7% and 51.1%, respectively. Patients experiencing an adverse event had a significantly lower DRR (P=0.019). In contrast, no significant differences were observed between biologic-naïve patients and those previously treated with biologic drugs (P=0.985). Patients carrying high-penetrance mutations exhibited a significantly higher DRR compared with those with low-penetrance variants (P=0.015). Adverse events were the only variable associated with a higher hazard of treatment withdrawal [hazard ratio (HR) 2.573 (CI: 1.223, 5.411), P=0.013] on regression analysis. A significant glucorticoid-sparing effect was observed (P Conclusions IL-1 inhibitors display an excellent long-term effectiveness in terms of DRR, and their survival is not influenced by the biologic line of treatment. They display a favourable safety profile, which deserves, however, a close monitoring given its impact on treatment continuation. Special attention should be paid to molecular diagnosis and mutation penetrance, as patients carrying low-penetrance variants are more likely to interrupt treatment.

Objective Our objective was to update the understanding of the development of paradoxical immune-mediated glomerular disorders (IGDs) in patients with rheumatic diseases treated with biologics and targeted synthetic drugs (ts-drugs). Methods A systematic literature review was performed by searching PubMed for articles published between 1 January 2014 and 1 January 2020 reporting on the development of IGD in adult patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or systemic lupus erythematosus (SLE) who were receiving biologics or ts-drugs. IGDs were classified on the basis of clinical, laboratory and histopathological data as (1) glomerulonephritis associated with systemic vasculitis (GNSV), (2) isolated autoimmune renal disorder (IARD) or (3) glomerulonephritis in SLE and in lupus-like syndrome (GNLS). The World Health Organization-Uppsala Monitoring Centre (WHO-UMC) system for standardized case causality assessment was applied to evaluate the causal relationship between IGD and specific drugs. The classification was based on a six-category scale, where the “certain” and “probable” categories were deemed clinically relevant relationships. Results The literature search retrieved 875 articles. Of these, 16 articles reported IGD data, for a total of 25 cases. According to the WHO-UMC assessment, the strength of the causal relationship between IGDs and investigated drugs was higher for anti-tumor necrosis factor-α agents (a clinically relevant relationship was found in four of six cases), abatacept (one of two cases), tocilizumab (two cases), ustekinumab (one case) and tofacitinib (one case) than for rituximab (nine cases), belimumab (three cases) or secukinumab (one case), which showed a weak causal relationship with these paradoxical events. No cases associated with apremilast or baricitinib were found. The retrieved cases were classified as 11 GNLS, seven IARD and seven GNSV. Conclusions Biologics and ts-drugs can cause IGDs. These events are rare, and the causative effect of a specific drug is hard to establish. When a patient is suspected of having an IGD, the drug should be discontinued, and treatment for the new-onset renal disorder should be promptly started.

Childhood obesity is a major public health concern. We wanted to evaluate the effectiveness of a multidisciplinary program based on healthy eating, exercise, cognitive-behavioral therapy, and health education to achieve weight loss and improve metabolic parameters in overweight and obese children. A randomized, controlled clinical trial with long-term follow-up (24 months) was conducted at a community care center in overweight and obese individuals aged 6–12 years. A sample of 108 children was divided into an experimental and a control group receiving a standard care program. The experimental groups received a 12-month interdisciplinary program; the results were evaluated at 4 months, the end of the intervention, and at follow-up 12 months later. Anthropometric and biological marker measurements related to metabolic alterations, dyslipidemia (based on total cholesterol), hyperglycemia, fasting glycaemia, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol in blood were recorded. The intervention had a significant effect ( p < 0.001) in terms of decreased body mass index, skinfolds, and waist and arm circumferences. These changes were accompanied by biochemical changes underlying an improvement in metabolic parameters, such as a significant reduction in total cholesterol, low-density lipoprotein-cholesterol, triglycerides, and hyperglycemia and a significant increase in high-density lipoprotein-cholesterol. These effects were still significant for markers of excess weight or obesity in the experimental group 12 months after the end of the intervention, suggesting that an enduring change in healthy lifestyles had been maintained period. This interdisciplinary, nurse-led program helped to reduce childhood and adolescent excess weight and obesity and had long-lasting effects.

BACKGROUND: Although targeted biological treatments have transformed the outlook for patients with rheumatoid arthritis, 40% of patients show poor clinical response, which is mechanistically still unexplained. Because more than 50% of patients with rheumatoid arthritis have low or absent CD20 B cells-the target for rituximab-in the main disease tissue (joint synovium), we hypothesised that, in these patients, the IL-6 receptor inhibitor tocilizumab would be more effective. The aim of this trial was to compare the effect of tocilizumab with rituximab in patients with rheumatoid arthritis who had an inadequate response to anti-tumour necrosis factor (TNF) stratified for synovial B-cell status. METHODS: This study was a 48-week, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial (rituximab vs tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis; R4RA) done in 19 centres across five European countries (the UK, Belgium, Italy, Portugal, and Spain). Patients aged 18 years or older who fulfilled the 2010 American College of Rheumatology and European League Against Rheumatism classification criteria for rheumatoid arthritis and were eligible for treatment with rituximab therapy according to UK National Institute for Health and Care Excellence guidelines were eligible for inclusion in the trial. To inform balanced stratification, following a baseline synovial biopsy, patients were classified histologically as B-cell poor or rich. Patients were then randomly assigned (1:1) centrally in block sizes of six and four to receive two 1000 mg rituximab infusions at an interval of 2 weeks (rituximab group) or 8 mg/kg tocilizumab infusions at 4-week intervals (tocilizumab group). To enhance the accuracy of the stratification of B-cell poor and B-cell rich patients, baseline synovial biopsies from all participants were subjected to RNA sequencing and reclassified by B-cell molecular signature. The study was powered to test the superiority of tocilizumab over rituximab in the B-cell poor population at 16 weeks. The primary endpoint was defined as a 50% improvement in Clinical Disease Activity Index (CDAI50%) from baseline. The trial is registered on the ISRCTN database, ISRCTN97443826, and EudraCT, 2012-002535-28. FINDINGS: Between Feb 28, 2013, and Jan 17, 2019, 164 patients were classified histologically and were randomly assigned to the rituximab group (83 [51%]) or the tocilizumab group (81 [49%]). In patients histologically classified as B-cell poor, there was no statistically significant difference in CDAI50% between the rituximab group (17 [45%] of 38 patients) and the tocilizumab group (23 [56%] of 41 patients; difference 11% [95% CI -11 to 33], p=0·31). However, in the synovial biopsies classified as B-cell poor with RNA sequencing the tocilizumab group had a significantly higher response rate compared with the rituximab group for CDAI50% (rituximab group 12 [36%] of 33 patients vs tocilizumab group 20 [63%] of 32 patients; difference 26% [2 to 50], p=0·035). Occurrence of adverse events (rituximab group 76 [70%] of 108 patients vs tocilizumab group 94 [80%] of 117 patients; difference 10% [-1 to 21) and serious adverse events (rituximab group 8 [7%] of 108 vs tocilizumab group 12 [10%] of 117; difference 3% [-5 to 10]) were not significantly different between treatment groups. INTERPRETATION: The results suggest that RNA sequencing-based stratification of rheumatoid arthritis synovial tissue showed stronger associations with clinical responses compared with histopathological classification. Additionally, for patients with low or absent B-cell lineage expression signature in synovial tissue tocilizumab is more effective than rituximab. Replication of the results and validation of the RNA sequencing-based classification in independent cohorts is required before making treatment recommendations for clinical practice. FUNDING: Efficacy and Mechanism Evaluation programme from the UK National Institute for Health Research. ispartof: LANCET vol:397 issue:10271 pages:305-317 ispartof: location:England status: published

OBJECTIVE To compare the effect of achievement and maintenance of Lupus Low Disease Activity State (LLDAS) and clinical remission (CR) in preventing early damage accrual in patients with systemic lupus erythematosus (SLE). METHODS In a monocentric cohort of 116 newly diagnosed SLE patients, LLDAS and CR achievement at 6 months (T1) after treatment initiation and their maintenance over the next 12 months were assessed. Early damage was recorded after 18 months of follow-up (T2) using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. Univariate and multivariate analyses were performed to evaluate the association of LLDAS and CR with early damage. RESULTS LLDAS was significantly more attained than CR both at T1 (42.2% versus 21.6% of patients; P < 0.001) and T2 (46.6% versus 31.9%; P = 0.022). The overlap rate between persistent LLDAS and persistent CR was 41.7% (n = 15). On multivariate analysis, achievement of CR (odds ratio [OR] 0.07 [95% confidence interval (95% CI) 0.01-0.59], P = 0.015) and LLDAS (OR 0.25 [95% CI 0.06-0.99], P = 0.049) at T1 were independently associated with lower accrual of early damage. Patients who achieved LLDAS (including CR) at T1 and steadily persisted in this condition until T2 developed significantly less damage compared to those who failed to maintain it during the T1-T2 interval (P = 0.003), those who achieved it later than T1 (P < 0.001), or those who had never been in this condition (P < 0.001). CONCLUSION Although CR is recommended as the primary treatment target in SLE, LLDAS represents a valid alternative in the early stage of SLE management. LLDAS and CR maintenance should be targeted to prevent damage.

Several cardiovascular (CV) risk algorithms are available to predict CV events in the general population. However, their performance in patients with rheumatoid arthritis (RA) might differ from the general population. This cross-sectional multicentre study aimed to estimate the 10-year CV risk using two different algorithms in a large RA cohort and in patients with osteoarthritis (OA).In a consecutive series of RA patients and matched OA controls without prior CV events, clinical and serologic data and traditional CV risk factors were recorded. The 10-year CV risk was assessed with the Systematic COronary Risk Evaluation (SCORE) and the "Progetto Cuore" algorithms.1,467 RA patients and 342 OA subjects were included. RA patients were more frequently diabetic (9.9% vs 6.4%; p=0.04) and smokers (20.4% vs 12.5%; p=0.002) but had lower prevalence of obesity (15% vs 21%; p=0.003). Dyslipidaemia was more prevalent in OA (32.5% vs 21.7%; p0.0001). The 10-year estimated CV risk was 1.6% (95%CI 1.3-1.9) in RA and 1.4% (95%CI 1.3-1.6) in OA (p=0.002) according to SCORE and 6.5% (95%CI 6.1-6.9) in RA and 4.4% (95%CI 3.9-5.1) in OA (p0.001) according to "Progetto Cuore". Regardless of the score used, RA patients had a 3- to-4-fold increased 10-year risk of CV events compared to OA subjects.RA patients have a significantly higher 10-year risk of CV events than OA subjects. In addition to effective disease control and joint damage prevention, specific protective measures targeting modifiable traditional CV risk factors should be implemented in RA.

Over the last few years, the landscape of treatments for axial spondyloarthritis (SpA) has been rapidly evolving, urging international scientific societies to draft or update existing clinical practice guidelines (CPGs) on the management of axial SpA. The Italian Society for Rheumatology (SIR) committed to provide revised and adapted evidence- and expert-based recommendations for the management of patients with axial SpA in Italy. A systematic approach to the adaptation of existing CPGs - the ADAPTE methodology - was adopted to obtain updated recommendations suitable for the Italian context. A systematic literature search was performed in Medline and Embase databases to find international CPGs and consensus statements with recommendations for the management of axial SpA published in the previous five years. A working group composed of rheumatologists with proven experience in the management of axial SpA and methodologists identified the key research questions which guided study selection and data extraction. Guideline quality was assessed using the Appraisal of Guidelines Research and Evaluation (AGREE) II tool. The Italian recommendations were developed by endorsing or adapting and rewording some existing recommendations. The draft of the recommendations was sent to a multidisciplinary group of external reviewers for comment and rating. Six original CPGs were selected and used to create this SIR CPG, which includes a final set of 14 recommendations covering the management of patients with axial SpA across the following domains: assessment, pharmacological and non-pharmacological treatment, and follow-up. The dissemination and implementation of these SIR recommendations are expected to support an evidencebased clinical approach to the management of patients with axial SpA in Italy.

Cognitive Behavioral Therapy (CBT) has long been recognized as a type of psychotherapy for the management of glycemic control and comorbid psychological disorders and symptoms in adults with diabetes, and has been previously reported with varying outcomes. The aim of this scoping review is to evaluate the randomized controlled trials (RCTs) in order to determine the effects of CBT on Type 2 diabetes mellitus (T2DM) patients regarding depressive and anxiety symptoms, diabetes distress, and quality of life. An extensive literature search was conducted of the Pubmed, Scopus, Cinahl and Medline electronic databases. The search yielded 349 studies, of which 12 eventually met the entry requirements for RCTs. The majority of the studies included in the current scoping review demonstrated the benefits of CBT intervention in the amelioration of depressive symptoms, diabetes-related distress and quality of life in patients with T2DM. However, some studies reported limited evidence to support the use of CBT as an adjuvant therapy. The considerable levels of heterogeneity associated with most RCTs included warrant caution when interpreting results. The findings of this scoping review demonstrate the positive impact of CBT on depressive symptoms and other psychological aspects of everyday life in patients with T2DM.

Objectives This study aims to investigate the factors associated with early discontinuation (within one year) of etanercept (ETA) in rheumatoid arthritis (RA) patients who began ETA as first biologic disease-modifying antirheumatic drug (bDMARD) and who were entered into the Gruppo Italiano di Studio sulla Early Arthritis (Italian Group for the Study of Early Arthritis; GISEA) registry. Patients and methods This registry-based cohort study included 477 RA patients (95 males, 382 females; median age 53 years; range 18 to 83 years) who began ETA as first bDMARD. Patient demographics, disease features and drugs were re-evaluated after 12 months. Baseline predictors of ETA discontinuation were estimated by univariate and multivariate analyses using Cox regression model. Results Seventy patients (14.7%) discontinued ETA during the first year (for inefficacy in 55.8%, adverse events in 28.6%, and other reasons in 6.5%). Concurrent conventional synthetic DMARDs (csDMARDs) were reported in 54.3% of patients, mainly methotrexate (MTX), while 52.4% of subjects took low doses of glucocorticoids. Patients stopping ETA more frequently showed one or more comorbidities, mainly cardiovascular diseases (28.6% vs. 15.7% in patients stopping and continuing ETA, respectively, p=0.009). The presence of comorbidities and a combination therapy with csDMARDs other than MTX were independent factors associated with early discontinuation of ETA at multivariate Cox analysis. Conclusion Although ETA demonstrated a high persistence in biologic-naive RA patients, about 15% of patients discontinued the treatment within 12 months. The presence of comorbidities and a combination therapy with csDMARDs other than MTX were the main factors for an early withdrawal of the drug.

Diabetic Foot Syndrome (DFS) is a common long-term complication of diabetes mellitus. DFS has recently been associated with adverse effects on brain function which could further impair the quality of life of these patients, as well as increase the social and economic burden, morbidity, and premature mortality of the disease. The current knowledge of neuropsychiatric alterations e.g. cognitive impairment, gait disorder, depression, and quality of life in patients with diabetic foot syndrome is summarized. The cognitive domains altered in DFS are executive function, memory, and psychomotor speed. Compared to diabetic patients without DFS, individuals with DFS present gait alterations caused by changes in several spatio-temporal parameters and lower-limb kinematics. The increased rates of anxiety and depression among patients with DFS were related to several factors, including female sex, a smoking habit, age under 50 years, and foot ulceration exceeding 7 months' duration. The role of infections and the use of preventive antimicrobial treatment need further studies regarding their effect on comorbid neuropsychiatric disorders. The care of these patients should include the prevention, detection and treatment of these neuropsychiatric disorders in order to improve their quality of life.

This study is primarily aimed at assessing serum changes on a large panel of proteins in patients with chronic back pain following spa therapy, as well as evaluating different spa therapy regimens as a preliminary exploratory clinical study. Sixty-six patients with chronic back pain secondary to osteoarthritis were randomly enrolled and treated with daily mud packs and bicarbonate-alkaline mineral water baths, or a thermal hydrotherapy rehabilitation scheme, the combination of the two regimens or usual medication only (control group), for two weeks. Clinical variables were evaluated at baseline, after 2 and 12 weeks. One thousand serum proteins were tested before and after a two-week mud bath therapy. All spa treatment groups showed clinical benefit as determined by improvements in VAS pain, Roland Morris disability questionnaire and neck disability index at both time points. The following serum proteins were found greatly increased (≥2.5 fold) after spa treatment: inhibin beta A subunit (INHBA), activin A receptor type 2B (ACVR2B), angiopoietin-1 (ANGPT1), beta-2-microglobulin (B2M), growth differentiation factor 10 (GDF10), C-X-C motif chemokine ligand 5 (CXCL5), fibroblast growth factor 2 (FGF2), fibroblast growth factor 12 (FGF12), oxidized low density lipoprotein receptor 1 (OLR1), matrix metallopeptidase 13 (MMP13). Three proteins were found greatly decreased (≤0.65 fold): apolipoprotein C-III (Apoc3), interleukin 23 alpha subunit p19 (IL23A) and syndecan-1 (SDC1). Spa therapy was confirmed as beneficial for chronic back pain and proved to induce changes in proteins involved in functions such as gene expression modulation, differentiation, angiogenesis, tissue repair, acute and chronic inflammatory response.

Purpose To explore the potential role of circulating endothelial cells (CECs) and their progenitors (EPCs) as biomarkers of disease activity and damage accrual in patients with Behcet's syndrome (BS), by using a standardised and reliable flow cytometry protocol. Patients and methods CECs and EPCs were assessed in 32 BS patients and 11 gender/age/smoking habits matched healthy controls (HC). They were identified by flow cytometry as alive/nucleated/CD45-negative/CD34-bright/CD146-positive and alive/nucleated/CD45-negative/CD34-bright/CD309-positive events, respectively. In BS patients, demographic and clinical features, including disease activity (assessed by Behcet's disease current disease activity form, BDCAF) and irreversible damage accrual (by the vasculitis damage index, VDI) were recorded. Uni- and multivariate analysis were performed to compare the CECs and EPCs concentrations in BS vs HC and to identify potential associations with demographic or clinical features. Results The CECs concentration was significantly higher in the BS patients than HCs [median (IQR) 15.0 (7.5-23.0) vs 6.0 (2.0-13.0) CECs/mL, p=0.024]. In BS patients, no significant associations were found between CECs and demographic features, present and past clinical manifestations, BDCAF score and ongoing treatment. A significant association was observed between CECs and organ damage, as assessed by the VDI (rho 0.356, p=0.045). Higher levels of CECs were especially associated with vascular damage [median (IQR) 23.0 (14.0-47.0) vs 13.0 (6.0-19.0) CECs/mL, p=0.011], including arterial aneurysm and stenosis, complicated venous thrombosis, cerebrovascular accident. The concentration of EPCs did not significantly differ between the BS and HC [median 26.5 (13.0-46.0) vs 19.0 (4.0-42.0) EPCs/mL, p=0.316] and no significant associations were observed between their levels and any clinical characteristic. Conclusion Our study suggests that the CECs concentration is significantly higher in BS than healthy subjects, and it mainly correlates with vascular damage. A longitudinal extension of the present study on a wider cohort would be useful to validate the potential role of CECs as a marker or, hopefully, predictor of vascular damage in BS.

Background People with severe mental disorders have a worse cancer prognosis, with higher mortality rates than the general population, and this could be partially attributed to a later detection. Breast cancer and colorectal cancer have mass population screenings in Spain, but the influence in early diagnosis is unknown in persons with severe mental disorders. Objective To compare the severity of breast and colorectal cancers at diagnosis in people with and without mental disorders. Methods This was an observational, retrospective, case-control study with 1:2 matching performed in Eastern Spain. Data were retrieved for analysis from electronic medical records. Results The study included 111 oncology patients (75 with breast cancer and 36 with colorectal cancer). Individuals with mental disorders had a significantly higher (P = .002) relative risk (odds ratio [OR], 3.93; 95% confidence interval [CI], 1.60-9.65) to be diagnosed with an advanced tumor stage (clinical stages IIIA, IIIB, IIIC, and IV), for both breast and colorectal cancers when analyzed separately. The variables associated with advanced cancer at the time of diagnosis were the presence of a previous mental disorder (OR, 4.67; 95% CI, 1.73-12.61) and older age (OR, 1.08; 95% CI, 1.02-1.14). Conclusions Individuals with severe mental disorders showed a higher risk of being diagnosed with breast and colorectal cancers at advanced stages. Implications for Practice: Cancer screening for earlier detection and intervention in people with severe mental disorders needs improvement. Mental health nurses, screening nurses, and oncology nurses could serve an essential role in increasing the screening adherence of this group of individuals.

Whole-body magnetic resonance imaging is constantly gaining more importance in rheumatology, particularly for what concerns the diagnosis, follow-up, and treatment response evaluation. Initially applied principally for the study of ankylosing spondylitis, in the last years, its use has been extended to several other rheumatic diseases. Particularly in the pediatric population, WB-MRI is rapidly becoming the gold-standard technique for the diagnosis and follow-up of both chronic recurrent multifocal osteomyelitis and juvenile spondyloarthritis. In this review, we analyze the benefits and limits of this technique as well as possible future applications.

Objectives: Specific anti-inflammatory and/or immunomodulating drugs (AIDs) can influence endothelial function which is often impaired in patients with rheumatoid arthritis (RA). We sought to determine whether overall patterns of AID usage are similarly associated with endothelial function.Methods: The reactive hyperaemia index (RHI), a marker of microvascular endothelial function, was measured in 868 RA patients reporting their intake of seven AIDs known to affect endothelial function. Latent class analysis (LCA) was performed to characterise patterns of AID usage. Models for 2–6 classes were compared using the AIC and BIC statistics and Lo-Mendell-Rubin likelihood ratio tests. Associations between the classes and RHI were adjusted for age, gender, body mass index, diabetes, HDL-cholesterol, LDL-cholesterol, family history of ischaemic heart disease, smoking status, RA duration, DAS28 score, steroid dose, existing hypertension, and C-reactive protein.Results: LCA identified five distinct AID usage classes: Class 1, generally low medication usage; Class 2, using either sulfasalazine or non-tumour necrosis factor (TNF) inhibitors; Class 3, methotrexate users; Class 4, TNF-inhibitor users; and Class 5, hydroxychloroquine users. The geometric mean for the RHI for subjects in classes 1 to 5 was 1.92, 1.81, 1.94, 2.10, and 2.07, respectively, with subjects in classes 4 and 5 having better endothelial function than subjects in class 2 (p = 0.003 for each). The glucocorticoid dosage did not influence the classes formed or the association between the classes and the RHI in sensitivity analyses.Conclusion: There were five broad patterns (classes) of AID usage in RA patients. The RHI was relatively lower in users of either sulfasalazine or non-TNF inhibitors. TNF inhibitors or hydroxychloroquine may counteract the negative effects of RA on endothelial function.

Frailty is a geriatric syndrome characterized by a decrease in physiological reserve and reduced resistance to stress, as a result of an accumulation of multiple deficits in physiological systems. Frailty increases the vulnerability to adverse events and is associated with the aging process. Several studies show an association between frailty syndrome and altered blood lymphocyte levels, which is therefore potentially useful for monitoring interventions to improve or delay frailty. The main objective of this review is to provide an analysis of the current evidence related to changes in lymphocyte counts and their associations with frailty syndrome. To that end, the literature published in this field until March 2021 was in several databases: PubMed, SCOPUS, and Cochrane. Eighteen studies analyzed the association between lymphocyte counts, lymphocyte subtypes, and frailty syndrome. Eighteen studies were analyzed, and most of them reported associations. Interestingly, the association between frailty syndrome and lower lymphocytes counts appears in different clinical conditions. Further studies are needed to determine the sensitivity of lymphocyte counts and lymphocyte subtypes in the diagnosis and monitoring of frailty syndrome, and for this measure to be used as a biomarker of frailty status.

Specific and high-quality evidence on the efficacy of the current targeted therapies for axial disease in psoriatic arthritis (axPsA) is still scarce. Indeed, almost all the cohorts investigated in clinical trials on PsA consisted of patients with peripheral arthritis, where a small number of them also had axial involvement. Only one randomized controlled trial was so far specifically designed to assess the efficacy of a biological disease-modifying antirheumatic drug (DMARD) in axPsA. For other biological and synthetic targeted DMARDs, the most specific evidence for treatment in axPsA is extrapolated frompost-hocanalyses based on PsA patients with concomitant peripheral and axial manifestations. Furthermore, the current trials andpost-hocanalysis on axPsA are affected by major limitations, including the lack of a widely accepted definition of axPsA and the lack of specific and validated outcome measures. Finally, poor data are available on the genetics of axPsA, although alleles differentially expressed in different patterns of axPsA might offer advantages in the prospective of personalized medicine in axPsA patients. Overall, this review suggests that there is an urgent need for more reliable evidence derived from studies specifically designed for axPsA and based on a validated definition of axPsA and on specific outcome measures.

Gastrointestinal (GI) involvement is almost universal in patients with systemic sclerosis (SSc) and is associated with significant disease-related morbidity and mortality.1 The entire GI tract can be involved and other disease features (eg, low mood, terminal organ failure and functional hand impairment) can result in significant nutritional impairment. Severe GI involvement has been reported to occur in ~10% of patients with SSc and often occurs early in the course of the disease.2 However, identification of patients at high risk of clinically significant weight loss is extremely challenging, including from the high prevalence of GI symptoms in patients with SSc. Therefore, there is a need to understand high-risk patients including potentially modifiable risk factors, with a view to early intervention strategies. Against this background, the aim of this study was to examine potential clinical risk factors of significant weight loss in patients with SSc. We performed an analysis of patients with SSc enrolled in the multinational, longitudinal European League Against Rheumatism (EULAR) Scleroderma Trials and Research (EUSTAR) database. In our study, we defined significant weight loss as 4.5 kg and/or least 5% of their body weight at 5 months onwards.3 Patients with a recorded second visit after 3 months and before 12 months were included in the analysis. We adopted a pragmatic approach (relevant to clinical practice) in …

The relationship between cognitive decline and androgen deprivation therapy (ADT) under luteinizing hormone-releasing hormone (LHRH) analogues is unclear, and there is a scarcity of longitudinal studies considering the interaction between cognition, depressive symptoms and sleep quality in men with prostate cancer (PCa) treated with ADT. This study aimed to determine if there were differences in the scores obtained in cognitive assessment, depressive symptoms, and sleep quality after one year of ADT and determine the interrelations between sleep, mood, and cognitive status. A prospective longitudinal observational study was designed, in which a cohort of men (mean age was 70.8 years) newly treated with androgen-deprivation therapy was assessed in the first six months of treatment and 12 months later. Analysis of cognitive function by the Mini-Mental State Examination (MMSE) scores indicated a significant (p &lt, 0.05) increase after one year of treatment and by the Brief Scale for Cognitive Evaluation (BCog) scores indicated no changes in the scores before and after one year of treatment. Analysis of depressive symptoms with the Geriatric Depression Scale and sleep quality with the Athens Insomnia Scale (AIS) scores showed significant (p &lt, 0.05) changes after one year of treatment with ADT, with men describing more depressive symptoms and more sleep disturbances. No statistically significant differences were found in the cognitive performance between men with impaired sleep or depression results and those without them. Our study showed no clinical evidence of the relationship between ADT under luteinizing hormone-releasing hormone (LHRH) analogues and cognitive deterioration in 1-year follow-up, but there are impairments in the sleep quality in men with PCa undergoing ADT and an increase in depressive symptoms which has important implications for clinicians as they would impair quality of life and adherence to treatment.

ObjectivesTo evaluate in a multicentric Italian cohort of patients with psoriatic arthritis (PsA) on secukinumab followed for 24 months: (1) the long-term effectiveness and safety of secukinumab, (2) the drug retention rate and minimal disease activity (MDA), (3) differences in the outcomes according to the biological treatment line: biologic-naïve patients (group A) versus multifailure (group B) patients.MethodsConsecutive patients with PsA receiving secukinumab were evaluated prospectively. Disease characteristics, previous/ongoing treatments, comorbidities and follow-up duration were collected. Disease activity/functional/clinimetric scores and biochemical values were recorded at baseline (T0), 6(T6), 12(T12) and 24(T24) months. Effectiveness was evaluated overtime with descriptive statistics; multivariate Cox and logistic regression models were used to evaluate predictors of drug-discontinuation and MDA at T6. Infections and adverse events were recorded.Results608 patients (41.28% men; mean (SD) age 52.78 (11.33)) were enrolled; secukinumab was prescribed as first-line biological treatment in 227 (37.34%) patients, as second (or more)-line biological treatment in 381 (62.66%). Effectiveness of secukinumab was shown with an improvement in several outcomes, such as Ankylosing Spondylitis Disease Activity Score (T0=3.26 (0.88) vs T24=1.60 (0.69) ;p=0.02) and Disease Activity Index for Psoriatic Arthritis (T0=25.29 (11.14) vs T24=7.69 (4.51); pgroup A showed lower Psoriasis Area Severity Index (p=0.04), erythrocyte sedimentation rate and C reactive protein (p=0.03 ;p=0.05) and joint count (p=0.03) compared with group B. At T24, MDA was achieved in 75.71% of group A and 70.37% of group B. Treatment was discontinued in 123 (20.23%) patients, mainly due to primary/secondary loss of effectiveness, and in 22 due to adverse events. Retention rate at T24 was 71% in the whole population, with some difference depending on secukinumab dosage (p=0.004) and gender (p=0.05).ConclusionsIn a real-life clinical setting, secukimumab proved safe and effective in all PsA domains, with notable drug retention rate.

Background and objectiveSystemic small vessel vasculitides carry an increased risk of acute arterial and venous thromboembolic events (AVTE); however, this risk has not been systematically explored in Eosinophilic Granulomatosis with Polyangiitis (EGPA). This study assessed the occurrence and main risk factors of AVTE among EGPA patients as compared to the general community from the population-based Bruneck cohort.MethodsWe conducted a retrospective multicenter cohort study on 573 EGPA patients. Clinical and serological data were collected at diagnosis. Occurrence of AVTE and time to the first AVTE after EGPA diagnosis were recorded. Age-standardized event rate (SER) of AVTE as compared to the reference cohort was assessed. Cox regression was applied to identify AVTE predictors.Results129 EGPA patients (22.5%) had AVTE, considered as potentially life-threatening in 55.8%. Seventy patients experienced an AVTE prior to diagnosis (of whom 58.6% in the two years before diagnosis) and 75 following EGPA diagnosis, of whom 56% in the two subsequent years. The SER of AVTE as compared to the reference cohort was 2.10 (95% CI 1.67-2.63). This risk was particularly increased in patients with history of AVTE and with a Birmingham Vasculitis Activity Score ≥20 at diagnosis. Patients receiving immunosuppression within 2 months of diagnosis were at lower risk, while antiplatelet or anticoagulant treatment did not confer measurable benefit.ConclusionEGPA is associated with AVTE in approximately one quarter of patients, particularly around diagnosis. Immunosuppressants seemed to exert a protective effect, while anticoagulant and antiplatelet agents did not.

The study of reduced respiratory muscle strengths in relation to the loss of muscular function associated with ageing is of great interest in the study of sarcopenia in older institutionalized individuals. The present study assesses the association between respiratory muscle parameters and skeletal mass content and strength, and analyzes associations with blood cell counts and biochemical parameters related to protein, lipid, glucose and ion profiles. A multicenter cross-sectional study was performed among patients institutionalized in nursing homes. The respiratory muscle function was evaluated by peak expiratory flow, maximal respiratory pressures and spirometry parameters, and skeletal mass function and lean mass content with handgrip strength, walking speed and bioimpedance, respectively. The prevalence of reduced respiratory muscle strength in the sample ranged from 37.9% to 80.7%. Peak expiratory flow significantly (p &lt, 0.05) correlated to handgrip strength and gait speed, as well as maximal inspiratory pressure (p &lt, 0.01). Maximal expiratory pressure significantly (p &lt, 0.01) correlated to handgrip strength. No correlation was obtained with muscle mass in any of parameters related to reduced respiratory muscle strength. The most significant associations within the blood biochemical parameters were observed for some protein and lipid biomarkers e.g., glutamate-oxaloacetate transaminase (GOT), urea, triglycerides and cholesterol. Respiratory function muscle parameters, peak expiratory flow and maximal respiratory pressures were correlated with reduced strength and functional impairment but not with lean mass content. We identified for the first time a relationship between peak expiratory flow (PEF) values and GOT and urea concentrations in blood which deserves future investigations in order to manage these parameters as a possible biomarkers of reduced respiratory muscle strength.

Identifying predictors of inadequate response to methotrexate (MTX) in rheumatoid arthritis (RA) is key to move from a “trial and error” to a “personalized medicine” treatment approach where patients less likely to adequately respond to MTX monotherapy could start combination therapy at an earlier stage. This study aimed to identify potential predictors of inadequate response to MTX in RA patients naïve to disease modifying anti-rheumatic drugs. Data from a real-life cohort of newly diagnosed RA patients starting MTX (baseline, T0) as first-line therapy were analyzed. Outcomes, assessed after 6 months (T1), were defined as failure to achieve a disease activity score 28 (DAS28) low disease activity (LDA) or a good/moderate response to MTX, according to the European League Against Rheumatism (EULAR) response criteria. Logistic regression was used to assess the associations between baseline variables and the study outcomes. Overall, 294 patients (60.5% females, median age 54.5 years) with a median disease duration of 7.9 months were recruited. At T1, 47.3% of subjects failed to achieve LDA, and 29.3% did not have any EULAR-response. In multivariate analysis, significant associations were observed between no LDA and current smoking (adjusted odds ratio [adjOR] 1.79, P = .037), female gender (adjOR 1.68, P = .048), and higher DAS28 (adjOR 1.31, P = .013); and between no EULAR-response and current smoking (adjOR: 2.04, P = .019), age (adjOR: 0.72 per 10-years increases, P = .001), and higher erythrocyte sedimentation rate (adjOR: 0.49; P = .020). By contrast, there were no associations between past smoker status and study outcomes. In summary, in our real-life cohort of disease modifying anti-rheumatic drug naïve RA patients, current smoking habit independently predicts inadequate response to MTX. This, together with other independent predictors of response to treatment identified in our study, might assist with personalized monitoring in RA patients. Further studies are required to investigate whether smoking quitting strategies enhance the therapeutic response to MTX.

Objective Metalloproteinase (MMP)-3 and MMP-12 are proteolytic enzymes especially implicated in joint inflammation. This study aims to evaluate their association with arthritis features and hand MRI abnormalities in patients with SLE. Methods Fifty SLE patients, with a mean (s.d.) age of 48.1 (14.6) years were tested for MMP-3 and MMP-12 serum levels, then further classified according to the presence of X-ray erosions and joint deformities. Eighteen RA patients aged 47.9 (11.8) and 14 healthy people aged 46.0 (11.0) were enrolled as control groups. A subgroup of 28 SLE patients underwent a dominant-hand MRI; the detected changes were classified and semi-quantitatively scored as capsular swelling, synovitis, edematous or proliferative tenosynovitis, bone oedema, bone erosions. Statistical analysis was performed using multiple regression models. Results MMP-3 were significantly higher in patients with Jaccoud’s arthropathy (JA) (22.1 ng/ml, P < 0.05) and independently associated with hsCRP serum levels (B-coeff 0.50; r = 0.30; P < 0.05). MMP-12 serum levels were significantly lower in patients with JA (0.18 ng/ml, P < 0.05) and inversely associated with the prednisone daily dose (B-coeff –0.03; r = −0.44; P < 0.01). Capsular swelling and edematous tenosynovitis, the most prevalent hand MRI changes in patients with JA, associated with higher MMP-3 (B-coeff 0.12; r = 0.66; P < 0.01 and B-coeff 0.08; r = 0.59; P < 0.01, respectively) and lower MMP-12 serum levels (B-coeff –7.4; r = −0.50; P < 0.05 and B-coeff –5.2; r = −0.44; P = 0.05, respectively). Conclusion Imbalanced MMP-3 and MMP-12 serum levels are influenced by inflammation and glucocorticoids in SLE patients and associated with JA and distinctive hand MRI changes.

Frailty syndrome is a functional state that includes a loss of ability to react to stressors, and is associated with poor outcomes, morbidity and premature mortality. The first line treatment in many men with prostate cancer (PCa) consists of an androgen-deprivation therapy (ADT) which can promote or favor frailty syndrome and ADT may therefore favor the progression of frailty over time. Among the pathophysiological bases of frailty, the presence of chronic low-grade inflammation has been associated with its adverse outcomes, but longitudinal studies are needed to validate these biomarkers. In this study, we prospectively evaluate frailty syndrome and blood inflammatory markers (IL1-beta, IL-6, IL-8, TNF alpha, C reactive protein) and leukocytes were measured at baseline and an average of 1 year later in PCa under ADT. Frailty was defined as having three or more of the following components: low lean mass, weakness, self-reported exhaustion, low activity level, and slow walking speed, prefrailty was defined as having one or two of those components. Multinomial regression analysis showed that among the inflammatory biomarkers, those significantly and repeatedly (baseline and follow-up time points) (p &lt, 0.05) associated with frailty syndrome were high IL-6 levels and low lymphocyte counts in blood. Other biomarkers such as IL-8, monocyte counts and C reactive protein were significantly associated with frailty syndrome (p &lt, 0.05) in cross-sectional analyses, but they do not predict frailty progression at 1 year-follow-up. Receiver operating characteristic curve analysis showed that both lymphocyte counts and IL-6 concentration significantly (p &lt, 0.05) (although moderately) discriminate PCa patients that progressed in the severity of frailty syndrome. IL-6 and lymphocytes count are possible biomarkers, useful for identifying frail patients and predicting the progression of frailty in PCa under ADT. Our study suggests the use of these biomarkers to guide clinical decisions on prostate cancer treatment based on a multidisciplinary approach.

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.

Background Biologic therapies have transformed the outlook for RA but the significant health economic impact of these therapies has highlighted the need to define predictive markers of response. Rituximab (RTX) is licensed for use following failure of csDMARDs and TNF inhibitor (TNFi) therapy. However, in this increasing therapeutically resistant cohort only 30% of patients achieve an ACR50 response. The observation in early RA that 50% of patients show low/absence of synovial B-cells prompted us to test the hypothesis that in these patients a biologic agent targeting alternative pathways maybe more effective. We report results from the first pathobiology-driven randomised controlled trial (RCT) in RA (R4RA) evaluating whether patient stratification according to the synovial B-cell rich/poor status enriches for response/non response to RTX. Methods R4RA is a phase IV open-label RCT conducted in 19 European centres recruiting patients failing or intolerant to csDMARD therapy and at least one TNFi. Synovial tissue was obtained at trial entry and used to classify patients as B-cell rich or poor using both histological and RNA-seq classification criteria. Patients were randomised to receive RTX or tocilizumab (TCZ). The study was powered to test in the B cell poor population superiority of TCZ over RTX at 16 weeks. The primary and co-primary end-points were defined respectively as Clinical Disease Activity Index (CDAI) ≥50% improvement from baseline and Major Treatment response (MTR)= CDAI improvement ≥ 50% and CDAI ≤10.1. Results The trial recruited to target (n = 164) with a power of 89.5%. In the B cell poor cohort a numerically higher number of patients achieved the primary endpoint and a significantly higher number of patients achieved co-primary endpoint (MTR). Classification of patients as B cell poor/rich according to RNA-seq criteria enhanced the difference between TCZ and RTX, with a significantly higher number of TCZ treated patients reaching both CDAI 50% improvement and CDAI MTR in the B-cell poor group. Conclusion In a RA B cell poor population failing csDMARDs and TNFi therapy, TCZ is more effective than RTX. This first biopsy-driven RCT suggests clinical utility for integrating molecular pathology profiling into treatment algorithms to allocate targeted therapies. Disclosures F. Humby: Honoraria; Roche, Pfizer. Grants/research support; Pfizer. P. Durez: BMS,Bristol-Myers Squibb, Celltrion, Eli Lilly, Hospira, Mundipharma, Pfizer, Samsung, Sanofi, UCB. M. Buch: Consultancies; Pfizer, Roche, UCB, AbbVie, Eli Lilly, Sandoz, and Sanofi. Grants/research support; Pfizer, Roche, UCB, AbbVie, Eli Lilly, Sandoz, and Sanofi. M. Lewis: None. M. Bombardieri: None. H. Rizvi: None. S. Kelly: None. L. Fossati: None. R. Hands: None. G. Giorli: None. A. Mahto: None. C. Montecucco: None. B. Lauwerys: None. V.C. Romao: None. A.G. Pratt: Member of speakers’ bureau; Eli Lilly and Janssen-Cilag Ltd. Grants/research support; Pfizer. S. Bugatti: None. N. Ng: None. F. Rivellese: None. P. Ho: None. M. Bellan: None. P. Sainaghi: None. P. Verschueren: None. N. Gendi: None. B. Dasgupta: Abbvie, BMS, GSK, Roche, Roche Chugai, Sanofi, Sanofi Aventis, Sanofi-Aventis. A. Cauli: BMS, Celgene, Lilly, Lilly MSD, MSD, Novartis, Pfizer, Sanofi, Sigma Wesseumen, UCB. C. John: None. A. Nerviani: None. G. Thornborn: None. D. Holroyd: None. M. Congia: None. C. Thompson: None. P. Reynolds: None. J. Cañete: None. R. J. Moots: Biogen, Bristol-Myers Squibb, Chugai, Novartis, Pfizer Inc, Roche, Sandoz, UCB. P.C. Taylor: AbbVie, Biogen, Celgene, Eli Lilly and Company, Fresenius, Fresenius SE & Co, Galapagos, Gilead. GlaxoSmithKline, Janssen, Lilly, Nordic Pharma, Pfizer, Pfizer Inc, Roche, Sanofi, UCB. C. Edwards: Abbvie, Biogen, BMS, Fresenius, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, UCB. J. Isaacs: None. P. Sasieni: None. J. E. Fonesca: None. E. Choy: AbbVie, Abbvie, Roche, Chugai, Amgen, Eli Lilly, Janssen, Novartis, Regeneron, R-Pharm and Sanofi, Amgen, Amgen, Roche, Chugai, Bristol-Myers Squibb, Eli-Lilly Janssen, Pfizer, Regeneron, Sanofi and UCB., AstraZeneca, Bio-Cancer, Bio-Cancer, Biogen, Novartis, Sanofi, Roche, Pfizer and UCB ,Biogen, BMS, Boehringer Ingelheim, Celgene, Chugai Pharma, Eli Lilly, Ferring Pharmaceuticals, GSK, Hospira, Janssen, Jazz Pharmaceuticals, Merck Sharp & Dohme, Merrimack Pharmaceutical, Napp, Novartis, Novimmune, ObsEva, Pfizer, Regeneron, Roche, R-Pharm, Sanofi, SynAct Pharma, Tonix, Union Chimique Belge. C. Pitzalis: None. NIHR have funded the study.

Background:The UPSTREAM (NCT03330769) is a 24-month multi-center prospective cohort study that primarily aims to evaluate the additional value of musculoskeletal ultrasound (msk-US) over clinical examination in predicting 6-month minimal disease activity in Psoriatic Arthritis (PsA). (1)Objectives:To develop and preliminarily validate an activity msk-US score and a damage msk-US score for PsA using the UPSTREAM database.Methods:Patients classified with PsA according to CASPAR criteria and starting a new course of therapy for clinically active peripheral joint disease were eligible. The information regarding objectives, study design, clinical and US assessment has already been published (1). The msk-US examination was performed in 42 joints, 36 tendons, 12 entheses and 2 bursae defined through a web-based exercise (2). The sonographic elementary lesions were allocated to disease activity [i.e. synovitis (sy), tenosynovitis (ts), peritendinitis (pt), bursitis (bs) all evaluated both in Grey Scale (GS) and Power Doppler (PD) and active enthesitis (en)] and to damage (i.e. joint erosion, bone proliferation, tendon tear, enthesophyte, calcification and irregular enthesis bone profile). Hands and feet X-ray were assessed using the modified Sharp-Van der Heijde (mSVH) score. A principal component (PC) analysis (PCA) was performed for each score and the number of PCs was defined by means of parallel analysis using baseline data. Each PC was normalized (n) taking into account the proportion between the observed value (e.g. sy-GS count) and the maximum expected value (e.g. 42 for sy-GS). Spearman’ correlation was used to investigate the construct and discrimination validity of the new scores.Results:Between February 2017 and May 2020, 312 PsA patients (155 men), with a mean (SD) age of 52.8 13.4, were enrolled from 19 centers; 22 expert sonographers were involved with substantial agreement for US lesions evaluated (k ≥0.7). The median [IQR] disease duration was 1.3 [0.1-6.1] years and the median [IQR] tender joint and swollen joint counts were 6 [3-13] and 2 [1-5], respectively. The weight derived from PCA for each sonographic lesions and the final equation for calculating the scores are reported in Figure 1 (1A activity and 1B damage). The final msk-US activity score [n(ts-GS + ts-PD)*2.87] + [n(bs-GS + bs-PD)*1.76] + [n(pt-GS + pt-PD)*1.43] + [n(active en)*1.00] + [n(sy-GS)*0.83] + [n(sy-PD)*0.45] has the best construct and discrimination validities according to a significant correlation with all clinical variables usually related to clinical activity (Table 1). The msk-US damage score correlated with mSVH score, HAQ and other clinical variables (Table 1).Table 1.VariablesMsk-US activity scoreMsk-US damage scoreSpearman correlationP-valueSpearman correlationP-valueESR0.1960.0020.0750.235CRP0.2090.0680.254TJC0.3380.286SJC0.3380.0720.221Dactylitis count0.284-0.0610.306LEI0.1940.0010.214Physician GA0.150.0120.0160.793Patient GA activity0.1380.018-0.0730.221Patient GA pain0.1990.001-0.0270.648HAQ0.2380.1460.014BASDAI0.2370.1750.003PSAID-90.70.0040.1480.013DAPSA0.3920.228Sharp van Der Heijde score0.1150.20.2660.003Figure 1.Conclusion:These newly developed and preliminary validated msk-US activity and damage scores could be used in patients with PsA in the context of observational and controlled trials.References:[1]Canzoni M et al. BMJ Open. 2018;8:e021942.[2]Zabotti A et al. Ann Rheum Dis 2018;77:1537–1538.Acknowledgements:Alberto Batticciotto; Oscar Massimiliano Epis; Luisa Arcarese; Luca Navarini; Marta Caprioli; Mirco Magnani; Roberta Ramonda; Marco Amedeo CimminoDisclosure of Interests:Alen Zabotti: None declared, Matteo Piga: None declared, Anna Zanetti: None declared, Marco Canzoni: None declared, nicola boffini: None declared, valentina picerno: None declared, Giovanni Zanframundo: None declared, Ettore Silvagni: None declared, Ivan Giovannini: None declared, BERND RAFFEINER: None declared, Palma Scolieri: None declared, Paola Mancini: None declared, Simone Parisi: None declared, Alessandra Bortoluzzi Grant/research support from: GSK, Garifallia Sakellariou Consultant of: Consultant for Abbvie and Novartis, Orazio De Lucia: None declared, Ilaria Tinazzi: None declared, Fabiana Figus: None declared, Luca Idolazzi Speakers bureau: Received grants as speaker for Eli Lilly, UCB, Celgene, MSD, Abbvie, Novartis, Paid instructor for: Paid instructor for UCB during Product specialist Meeting, Mariagrazia Lorenzin: None declared, Sara Zandonella Callegher: None declared, Alberto Cauli: None declared, Greta Carrara: None declared, Carlo Alberto Scirè: None declared, Annamaria Iagnocco: None declared

ObjectiveTo establish whether synovial pathobiology improves current clinical classification and prognostic algorithms in early inflammatory arthritis and identify predictors of subsequent biological therapy requirement.Methods200 treatment-naïve patients with early arthritis were classified as fulfilling RA1987 American College of Rheumatology (ACR) criteria (RA1987) or as undifferentiated arthritis (UA) and patients with UA further classified into those fulfilling RA2010 ACR/European League Against Rheumatism (EULAR) criteria. Treatment requirements at 12 months (Conventional Synthetic Disease Modifying Antirheumatic Drugs (csDMARDs) vs biologics vs no-csDMARDs treatment) were determined. Synovial tissue was retrieved by minimally invasive, ultrasound-guided biopsy and underwent processing for immunohistochemical (IHC) and molecular characterisation. Samples were analysed for macrophage, plasma-cell and B-cells and T-cells markers, pathotype classification (lympho-myeloid, diffuse-myeloid or pauci-immune) by IHC and gene expression profiling by Nanostring.Results128/200 patients were classified as RA1987, 25 as RA2010 and 47 as UA. Patients classified as RA1987 criteria had significantly higher levels of disease activity, histological synovitis, degree of immune cell infiltration and differential upregulation of genes involved in B and T cell activation/function compared with RA2010 or UA, which shared similar clinical and pathobiological features. At 12-month follow-up, a significantly higher proportion of patients classified as lympho-myeloid pathotype required biological therapy. Performance of a clinical prediction model for biological therapy requirement was improved by the integration of synovial pathobiological markers from 78.8% to 89%–90%.ConclusionThe capacity to refine early clinical classification criteria through synovial pathobiological markers offers the potential to predict disease outcome and stratify therapeutic intervention to patients most in need.

Demyelinating syndrome (DS) is a rare manifestation of systemic lupus erythematosus (SLE) (1%) with high clinical heterogeneity and potentially severe prognosis. It can represent a diagnostic and therapeutic challenge for clinicians. A recent study described 5 different patterns of demyelinating disease presentation, characterised by specific clinical, laboratory and brain and spine magnetic resonance imaging abnormalities: 1) neuromyelitis optica; 2) neuromyelitis optica spectrum disorders; 3) DS prevalently involving the brain; 4) DS prevalently involving the brainstem; 5) clinically isolated syndrome. In this review we briefly discuss typical characteristics of each DS presentation in SLE and we describe 5 illustrative clinical cases, one for each subset of DS, considering both diagnostic and therapeutic options.

Demyelinating syndrome secondary to systemic lupus erythematosus (DS-SLE) is a rare encephalomyelitis burden with a high risk of disability and death. We report on a 49-year-old Caucasian woman with systemic lupus erythematosus (SLE) complicated by severe cognitive dysfunction, brainstem disease, cranial nerve palsies, weakness and numbness in limbs and multiple discrete magnetic resonance imaging (MRI) areas of damage within the white matter of semioval centers, temporal lobe, external capsule, claustrum, subinsular regions and midbrain. She also had multiple mononeuritis diagnosed through sensory and motor nerve conduction study. She was diagnosed with severe DS-SLE prominently involving the brain and was treated with 500 mg methylprednisolone (PRE) pulses for 3 consecutive days, followed by one single pulse of 500 mg cyclophosphamide, and 1 g rituximab, which was then repeated 14 days later. PRE 25 mg/day, rapidly tapered to 7.5 mg/day in 6 months, and mycophenolate mofetil 1 g/day were prescribed as maintenance therapy. She had progressive and sustained improvement in neurological symptoms with almost complete resolution of brain MRI lesions after 1 year. B-cell depleting therapy could be considered as a possible alternative to standard of care in the management of severe inflammatory neuropsychiatric SLE but it should be associated with a conventional immunosuppressant as maintenance treatment to reduce the risk of flare and reduce corticosteroids dose.

Background:Few studies have examined the correlation between clinical demographic and laboratory parameters with peripherical radiological erosive disease in PsA pts.Objectives:To examine the association between clinical, demographical and laboratory data and the presence of radiographic erosions (RE) in the peripheral joints of psoriatic arthritis (PsA) pts.Methods:A cross-sectional study was conducted in consecutive patients with PsA afferring 7 rheumatological italian tertiary care centers. Demographical, clinical, laboratory and imaging data were collected according to a standardized protocol. A patient was considered as affected by erosive disease (ED) if at least one joint presented radiographic erosions at hand and/or feet rx examination. Patients with ED at early rx examination (before 5 y from disease diagnosis) were considered as early ED (EED) pts and pts without ED at 6 y or more rx examination from disease diagnosis were considered as not EED (NEED).The association between the presence of joint erosions and demographical, clinical and laboratory data was assessed using logistic regression analysis. The results were expressed in terms odds ratios (OR), and 95% confidence intervals (CI).Results:Rx hand and feet examination were available for analysis in 492/794 (39.9 % females, mean age 53.3 ± 13.2 y, mean PsA duration 16.9 ± 16.8 y, ED 171 pts). 48 pts had EED and 133 pts had NEED. At univariate analyses factors significantly associated with EED (p < 0.20) were PsA duration (OR=0.979,95%CI 0.953-1.006, p = 0.119), diagnostic delay (OR=1.077, 95%CI 1.018-1.138, p = 0.009), history of peripheral enthesitis (OR=2.308,95%CI 0.904-5.888, p= 0.080), hypertrigliceridemia (OR=2.756,95%CI 0.997-7.618, p = 0.0.051), hypercholesterolemia (OR=1.687, 95%CI 0.777-3.661, p = 0.186), hyperuricemia (OR=0.450, 95%CI 0.174-1.166, p = 0.10), use of biological agents (OR=1.712, 95%CI 0.873-3.355, p=0.118). Factors significantly associated with EED at multivariate regression analyses were diagnostic delay (OR = 1.11, 95% CI: 1.01, 1.22), history of enthesitis (OR = 3.15, 95% CI: 1.23, 8.22), use of therapy with biological agents (OR = 3.60, 95% CI: 1.31, 9.85) with protective effect of hyperuricemia (OR = 0.25, 95% CI: 0.07, 0.90).Conclusion:The presence of EED in a group of consecutive PsA patients is correlated to diagnostic delay and history of enthesitis. Longitudinal study may confirm these associations.Disclosure of Interests:Maria Grazia Catanoso: None declared, Pierluigi Macchioni: None declared, Antonio Marchesoni Speakers bureau: Abbvie, Pfizer, UCB, Novartis, Celgene, Eli Lilly, Salvatore D’Angelo Speakers bureau: AbbVie, Biogen, BMS, Celgene, Janssen, Lilly, MSD, Novartis, Pfizer, Sanofi, and UCB, Roberta Ramonda Speakers bureau: Novartis, Celgene, Janssen, Pfizer, Abbvie, Lilly, Alberto Cauli: None declared, fabio perrotta: None declared, Roberto Bortolotti: None declared, mariana lofrano: None declared, laura rotunno: None declared, maria grazia lorenzin: None declared, Guido Valesini: None declared, giovanni mathieu: None declared, Giuseppe Paolazzi: None declared, Carlo Salvarani Grant/research support from: consulting and investigator fees from Abbvie, Pfizer, MSD, Roche, Celgene, Novartis, Consultant of: consulting and investigator fees from Abbvie, Pfizer, MSD, Roche, Celgene, Novartis

Background The aim of this study was to evaluate the prevalence and clinical significance of Anti-neuronal antibodies (AnAb) in a cohort of neuropsychiatric (NP) Systemic Lupus Erythematosus (SLE) patients. Methods Overall, 28 SLE patients (age 45.6 ± 14.4 years) with inflammatory neuropsychiatric syndromes, classified according to existing criteria (1, 2) were enrolled and serum samples were collected before starting treatment for the specific NP event; 41 consecutive SLE patients (44.2 ± 14.2 years) without NP involvement, 22 Multiple Sclerosis patients (37.9 ± 11.0 years) and 82 healthy subjects (44.8 ± 15.0 years) served as controls. Search for AnAb was performed by tissue-based immunohistochemistry assays (IHC) on male Sprague Dawley rat’s brain sections and confirmed by cell-based immunocytochemistry assays on SH-SY5Y (human neuroblastoma) cell cultures. The association between serum positivity for AnAb by IHC and a large panel of data (demographic, serologic, SLEDAI, conventional brain MRI, treatment) was investigated by univariate analysis. Multivariate models were fitted with covariates with p Results AnAb were detected in 23 (82.1%) NPSLE patients and in 16 (39.0%) SLE patients without NP involvement resulting in 82% specificity (95%CI 71%-90%) and 61% sensitivity (95%CI 48%-72%) in differentiating NPSLE from SLE without NP involvement. None of the sera from MS patients (0%) and healthy subjects (0%) showed AnAb. Serum AnAb by IHC were independently associated with NPSLE (p Conclusion AnAb are significantly more frequent in patients with NPSLE than SLE. Further studies are needed to identify the unknown neuronal antigens targeted by AnAb in SLE patients.

Treating sarcopenia in older individuals remains a challenge, and nutritional interventions present promising approaches in individuals that perform limited physical exercise. We assessed the efficacy of leucine administration to evaluate whether the regular intake of this essential amino acid can improve muscle mass, muscle strength and functional performance and respiratory muscle function in institutionalized older individuals. The study was a placebo-controlled, randomized, double-blind design in fifty participants aged 65 and over (ClinicalTrials.gov identifier NCT03831399). The participants were randomized to a parallel group intervention of 13 weeks&rsquo, duration with a daily intake of leucine (6 g/day) or placebo (lactose, 6 g/day). The primary outcome was to study the effect on sarcopenia and respiratory muscle function. The secondary outcomes were changes in the geriatric evaluation scales, such as cognitive function, functional impairment and nutritional assessments. We also evaluated whether leucine administration alters blood analytical parameters and inflammatory markers. Administration of leucine was well-tolerated and significantly improves some criteria of sarcopenia in elderly individuals such as functional performance measured by walking time (p = 0.011), and improved lean mass index. For respiratory muscle function, the leucine-treated group improved significantly (p = 0.026) in maximum static expiratory force compared to the placebo. No significant effects on functional impairment, cognitive function or nutritional assessment, inflammatory cytokines IL-6, TNF-alpha were observed after leucine administration compared to the placebo. The use of l-leucine supplementation can have some beneficial effects on sarcopenia and could be considered for the treatment of sarcopenia in older individuals.

Background/Purpose To compare the independent effect of achievement and maintenance of lupus low disease activity state (LLDAS) and clinical remission (CR) in preventing early damage accrual in the early stage of systemic lupus erythematosus (SLE) management. Methods In a monocentric inception cohort of 116 newly diagnosed SLE patients, LLDAS and CR achievement at 6 months (T1) after treatment initiation and their maintenance over the next 12 (T2) months were assessed. Early damage was assessed (T2) using the SLICC/damage index. Uni- and multivariate analysis were performed to evaluate the association of LLDAS and CR with early damage. Results LLDAS achievement was significantly more frequent than CR both at T1 (42.2% vs. 21.6%, p The overlap between persistent LLDAS and persistent CR between T1 and T2 was observed in 41.7% of cases. On multivariate analysis, the achievement of CR (OR 0.1, 95%CI 0.01–0.59, p=0.015) and LLDAS without CR (OR 0.2; 95%CI 0.06–0.99, p=0.049) at T1, as well as younger age at onset (OR 0.95, 95%CI 0.91–0.98, p=0.004), were negatively associated with early damage. Patients who achieved LLDAS at T1 and steadily persisted in this condition until T2 developed significantly less damage compared to those who failed to maintain it during the T1-T2 interval (p=0.003), those who achieved it later than T1 (p Conclusions Although CR is recommended as the primary treatment target in SLE, LLDAS may represent a valid alternative in the early stage of SLE management. LLDAS and CR maintenance should be targeted to prevent damage.

Background: Reducing the burden of beta-amyloid accumulation and toxic autoimmunity-related proteins, one of the recognized pathophysiological markers of chronic and common neurological disorders such as Alzheimer’s disease (AD) and multiple sclerosis (MS), may be a valid alternative therapy to reduce their accumulation in the brain and thus reduce the progression of these disorders. The objective of this review was to evaluate the efficacy of plasmapheresis (PP) in AD and chronic progressive MS patients (in terms of improving clinical symptoms) and to analyze its safety and protocols. Methods: Articles related to this topic and published without time limitations in the Medline, and Cochrane databases were reviewed. Results: In AD patients, PP reduced amyloid beta (Aβ) levels in the brain, accompanied by a tendency towards cognitive stabilization, and improved language and verbal fluency. In regards to structural and functional brain changes, PP reduced brain volume and favored the stabilization, or absence, of the progression of perfusion. In chronic progressive form of MS patients, PP improved neurological deficits in 20−70% of patients with a chronic progressive form of MS, and restored interferon (IFN) responsiveness, which was not accompanied by any image change in brain plaques. Conclusions: Therapeutic plasmapheresis with albumin replacement is a promising strategy for reducing Aβ mediated toxicity and slowing the progression of the disorder. Some patients with chronic progressive forms of MS show improvement in neurological deficits. The features of AD and MS patients who benefit most from this approach need further research.

Background To compare the patients’ and physician’s global assessment of disease activity in Behçet’s syndrome (BS) and investigate the frequency, magnitude, and determinants of potential discordance. Methods A total of 226 adult BS patients with a median (IQR) age of 46.9 (35.6–55.2) years were enrolled across Italy, Greece, Portugal, and Spain. Demographic, clinical, and therapeutic variables, as well as the patient reported outcomes, were collected at the recruitment visit. The physical (PCS) and mental (MCS) component summary scores of the Short Form Questionnaire 36 (SF-36) and the Behçet’s syndrome Overall Damage Index (BODI) were calculated. Disease activity was assessed by the patients’ (PtGA) and physician’s global assessment (PGA) in a 10-cm visual analog scale, as well as the Behçet Disease Current Activity Form (BDCAF). Discordance (∆) was calculated by subtracting the PGA from the PtGA and defined as positive (PtGA>PGA) and negative (PtGA Results Median PtGA and PGA scores were 2.0 (0.3–5.0) and 1.0 (0.0–3.0) cm, respectively. The discordance prevalence varied (from 29.6 to 55.3%) according to the cutoff applied, and the majority (> 80%) of disagreements were due to patients rating higher their disease activity. Higher values of BDCAF were associated to increased rate of positive discordance. When BDCAF = 0, the median (IQR) values of PtGA and PGA were 0.2 (0–2) and 0 (0–1), respectively. PCS (adjusted odds ratio (adjOR) 0.96 per unit, 95% CI 0.93–0.98, p = 0.006) and MCS (adjOR 0.96 per unit, 95% CI 0.93–0.99, p = 0.003) were independently associated with positive discordance using both cutoffs. Active ocular involvement emerged as a potential determinant of negative discordance (adjOR 5.88, 95% CI 1.48–23.30, p = 0.012). Conclusions PtGA and PGA should be considered as complementary measures in BS, as patients and physicians may be influenced by different factors when assessing active disease manifestations. Particularly, PtGA may be a useful tool in the assessment of BS disease activity, as it carries a low risk to misclassify an inactive disease, and may allow to capture aspects of the patient’s health that negatively affect his well-being and the treatment.

To evaluate the clinical effectiveness of golimumab in biologic inadequate responder (IR) patients with Rheumatoid arthritis (RA), Spondyloarthritis (SpA), and Psoriatic arthritis (PsA).We analyzed 1424 patients on golimumab from the GISEA registry. Drug survival was estimated by Kaplan-Meier analysis in biologic-naïve, 1-biologic IR, ≥2-biologics IR patients. Hazard ratios (HRs) of discontinuing golimumab at 2 years were assessed by multivariate Cox regression. Patients achieving CDAI based low disease activity (LDA) or BASDAI4 were calculated at 6 and 12 months.In RA (n.370), the 2-years survival on golimumab was 61.4% in 1-biologic IR, 51.9% in≥2-biologics IR, and 73.1% in biologic-naive patients (P=0.002 vs≥2-biologics IR). In SpA (n.502), the survival was similar among 1-biologic IR (80%), ≥2-biologics IR (76.5%), and biologic-naive (74.6%) patients (P0.05). In PsA (n.552) the survival was 72% in 1-biologic IR, 72.5% in≥2-biologics IR, and 71.8% in naïve-biologic (P0.05). Predictors of golimumab discontinuation were monotherapy (HR 1.65) for RA, female gender for SpA (HR 2.48) and PsA (HR 1.57). In RA, patients on CDAI-LDA were lower in 1-biologic IR (40%) or≥2 biologics IR (40%) than in biologic-naïve (60%) group at 6 months (P=0.02), but no difference was observed at 12 months. In PsA and SpA, the percentage of patients on CDAI-LDA or BASDAI4 at 6 months was almost identical across the subgroups.Golimumab had similar effectiveness in biologic-failure and biologic-naïve SpA and PsA, but seems to be less effective in multi-failure RA patients, especially as monotherapy. The best outcomes were seen in male patients.

Background:Identifying psoriatic arthritis (PsA) among people with psoriasis is often challenging due to low specificity of symptoms at early PsA stage and/or delayed referral to the rheumatologist. Screening instruments -assisting the dermatologist to decide when rheumatological assessment is beneficial- have potential to reduce the diagnostic delay.Objectives:To evaluate the accuracy of a dermatologist-filled-out questionnaire designed for screening PsA among psoriatic patients under dermatology care.Methods:HERACLES is a multicentre, cross-sectional study running at 9 Italian dermatology and rheumatology tertiary centres. All participants were under dermatology care for skin psoriasis. Previous diagnosis of PsA precluded eligibility. Dermatologists at each site assessed consecutive psoriatic subjects, filled in the specifically-designed HERACLES questionnaire (HQ, Figure 1) and finally referred the participants to rheumatologists for clinical evaluation. All participants filled in the ToPAS, PASE, PEST and EARP questionnaires. Rheumatologists assessed the participants regardless of the questionnaires’ scores. The gold standard applied to assess the instruments’ accuracy was the diagnosis of PsA as established by the rheumatologists. ROC curve analysis evaluated the performance of the scores associated with the clinical criteria listed in the HQ, estimating the sensitivity and specificity of different cut-off levels. Further exploratory ROC curve analysis compared HQ performance to that of the other four questionnaires tested.Figure 1.Results:Out of 759 subjects enrolled, 524 (69%) attended rheumatology assessment. Rheumatologists diagnosed PsA in 73/524 patients (13.9%, Figure 2). Mean age was 53 (SD 16) years and 46% were female. Mean psoriasis duration was 20 (SD 19) years. The area under the ROC curve of HQ was 0.775. The HQ score cut-off value of 2 yielded a sensitivity of 92% and a specificity of 47%; a cut-off value of 3 yielded a sensitivity of 66% and a specificity of 75%. The comparison between the ROC curve of the HQ and those of the other four questionnaires evaluated did not show any significant difference (p=0.523 versus TOPAS; p=0.201 versus PASE; p=0.345 versus PEST and p=0.240 versus EARP).Figure 2.Conclusion:The HERACLES questionnaire, a tool designed for dermatologists, showed good sensitivity and specificity in identifying PsA cases among subjects with cutaneous psoriasis.Acknowledgments:The HERACLES project was supported by a research grant from FIRA and Pfizer Italia SRLDisclosure of Interests:Gabriele De Marco: None declared, Maria Manara Consultant of: Consultant and/or speaker for Eli-Lilly, MSD, Sanofi-Genzyme, Novartis, Alfa Wasserman and Cellgene, Speakers bureau: Consultant and/or speaker for Eli-Lilly, MSD, Sanofi-Genzyme, Novartis, Alfa Wasserman and Cellgene, Paolo Gisondi: None declared, Luca Idolazzi: None declared, Roberta Ramonda Speakers bureau: Novartis, Celgene, Janssen, Pfizer, Abbvie, Lilly, Stefano Piaserico: None declared, Alberto Cauli: None declared, Marco Amedeo Cimmino: None declared, Veronica Tomatis: None declared, Carlo Salvarani: None declared, Rosanna Scrivo: None declared, Anna Zanetti: None declared, Greta Carrara: None declared, Carlo Alberto Scirè: None declared, Angelo Cattaneo: None declared, Antonio Marchesoni Speakers bureau: Abbvie, Pfizer, UCB, Novartis, Celgene, Eli Lilly

ObjectiveTo develop and validate the evidence-based and consensus-based Behçet’s Syndrome Overall Damage Index (BODI).MethodsStarting from 120 literature-retrieved preliminary items, the BODI underwent multiple Delphi rounds with an international multidisciplinary panel consisting of rheumatologists, internists, ophthalmologists, neurologists, and patient delegates until consensus was reached on the final content. The BODI was validated in a cross-sectional multicentre cohort of 228 patients with Behçet’s syndrome (BS) through the study of (a) correlation between BODI and Vasculitis Damage Index (VDI) and (b) correlation between BODI and disease activity measures (ie, Behçet’s Disease Current Activity Form (BDCAF), Physician Global Assessment (PGA), Patient Global Assessment (PtGA)), c) content and face validity and (d) feasibility.ResultsThe final BODI consists of 4 overarching principles and 46 unweighted-items grouped into 9 organ domains. It showed good to excellent reliability, with a mean Cohen’s k of 0.84 (95% CI 0.78 to 0.90) and a mean intra-class correlation coefficient of 0.88 (95% CI 0.80 to 0.95). Overall, 128 (56.1%) patients had a BODI score ≥1, with a median score of 1.0 (range 0–14). The BODI significantly correlated with the VDI (r=0.693, pConclusionsPending further validation, the BODI may be used to assess organ damage in patients with BS in the context of observational and controlled trials.

Background Disease activity evaluation is mandatory according to the OMERACT Core Set of Domains for Behcet’s Syndrome (BS). Poor data are available on Patient (PtGA) and physician (PGA) global assessment of disease activity in BS. Objectives To assess PtGA performance in patients with BS and how different disease manifestations influence the patient and physician’s perception of disease activity. Methods A multicenter cross-sectional cohort of consecutive BS patients was enrolled. Disease activity was evaluated by PtGA, PGA and the Behcet’s disease current activity form (BDCAF). PtGA and PGA were assessed trough a single question (“How active was BS during the last week?”) in a 10-cm visual analogic scale. Health related quality of life (HRQoL) perception was evaluated by the Physical Component Summary (PCS) and the Mental Component summary (MCS) of the SF36v2 questionnaire. Correlation between PtGA, PGA, BDCAF and between them and SF36v2 component summaries was assessed trough the Spearman’s correlation coefficient (rho). Two separated multiple regression models were built to measure the independent effect (β regression) of each active clinical manifestation on PtGA and PGA. Results Overall, 226 BS patients from 5 Mediterranean Countries were enrolled. Out of them, 111 (49.1%) were males and the median (IQR) age and disease duration were 46.9 (35.6-55.2) and 11.7 (5.9-20.8) years, respectively. The median (IQR) value of PtGA, PGA and BDCAF were 2.0 (0.3-5.0), 1.0 (0.0-3.0) and 3.0 (0.0-5.0), respectively. PtGA significantly correlated (Figure) with both PGA (rho 0.759. p 0.001) and MCS (rho -451. p > 0.001). Conclusion PtGA seems to be a valid outcome measure in BS and should be considered as a separate outcome measure or better be included in composite index for overall disease activity evaluation. Disclosure of Interests Alberto Floris: None declared, Matteo Piga: None declared, Gerard Espinosa: None declared, Nikolaos Kougkas: None declared, Andrea Lo Monaco: None declared, Giuseppe Lopalco Speakers bureau: SOBI, BMS, Ida Orlando: None declared, Vittorio Pirani: None declared, Ernestina Santos: None declared, Luisa Serpa Pinto: None declared, George Bertsias: None declared, Luca Cantarini: None declared, Alberto Cauli: None declared, Ricard Cervera: None declared, Joao Correia: None declared, Marcello Govoni: None declared, Florenzo Iannone Consultant for: F Iannone has received consultancy fees and/or speaker honoraria from Pfizer, AbbVie, MSD, BMS, Novartis, Lilly, UCB outside this work, Speakers bureau: F Iannone has received consultancy fees and/or speaker honoraria from Pfizer, AbbVie, MSD, BMS, Novartis, Lilly, UCB outside this work, Ana Martins da Silva: None declared, Piergiorgio Neri: None declared, Carlos Vasconcelos: None declared, Alessandro Mathieu: None declared

Background Methotrexate (MTX) is the gold standard as first line treatment in rheumatoid arthritis (RA). Identifying predictors of response to MTX should be crucial in the view of a personalized therapy. Objectives To identify prevalence and potential clinical baseline predictors of inadequate response (IR) to MTX in RA patients naive to disease modifying anti-rheumatic drugs (DMARDs)*. Methods Data of 233 consecutive RA patients (according to ACR/EULAR 2010 criteria) naive to traditional and biologic DMARDs, attending the AOU University Clinic, Rheumatology Unit, Monserrato (Cagliari), Italy, were analyzed. Table 1 shows baseline demographic, clinical and serological characteristics of the cohort. Patients failing to reach low disease activity state (DAS 28 > 3.2) at 6 months (T1) since the beginning of MTX (T0) or patients undergoing therapeutic modification for persistently high disease activity (switch or addition of other traditional or biological DMARDs) before T1 were considered as IR. By univariate analysis, demographic, clinical and serological factors recorded at T0 were evaluated as potential predictors of IR at T1. Afterwards, factors with p Results At T1, 104 patients (44.6%) were classified as IR to MTX. In univariate analysis, factors significantly associated with IR were: female gender (69.2% vs. 54.3%; p=0.02), condition of ”current smoker” (22.1% vs. 10.9%; p=0.012), ESR [median (IQR): 30.0 (19.0-48.0) vs. 40.0 (25-62); p=0.035] and DAS28 (mean ± standard deviation: 5.5 ± 1.1 vs. 5.2 ± 1.3; p=0.037). High-titre positivity for RF and/or ACPA (57.3% vs. 45.9%; p=0.095) and high cumulative steroids dose [852 mg (300-1200) vs. 691 mg (0-150); p=0.071] were numerically higher in IR. In multivariate analysis, the ”current smoker” condition was confirmed as the only independent factor associated with IR to MTX after 6 months of treatment (OR: 2.333, 95% CI: 1.132-4.805; p=0.022). No significant association between ex-smoker status and IR to MTX was demonstrated. This result was confirmed even after stratification of ex-smokers over the time since smoking stop. Finally, for both current smokers and ex-smokers, the duration of exposure to cigarette smoking did not show any significant association with IR. Conclusion In this RA cohort, the condition of ”current smoker” was the only predictor of IR to MTX. This observation, together with the lack of association between previous smoking habit and IR to MTX, further prompt to recommend cessation of cigarette smoking in patients with RA who begin treatment with MTX. Acknowledgement This study was supported by an unconditioned Research grant from Pfizer Inc. Disclosure of Interests None declared

To evaluate the role of peripheral inflammation (leukocyte differential count, the proinflammatory cytokines IL-beta, TNF-α, IL-6, IL-8, and the inflammatory markers fibrinogen and C-reactive protein [CRP]) in frailty syndrome in patients with prostate cancer (CaP) undergoing antiandrogen therapy (ADT).A total of 46 men between 51 and 92 years of age with CaP and receiving ADT were classified as frail, prefrail or robust according to the Fried scale. A geriatric assessment was performed, based on the Minimental State Examination for cognitive function, the Barthel index for basic activities of daily living, the Yesavage scale for geriatric depression, and the Athens insomnia scale. In addition, blood samples were collected to assess peripheral inflammation biomarkers including proinflammatory cytokines, fibrinogen, CRP and leukocyte differential count, as well as other biochemical and hematological parameters.A significant negative correlation between the severity of frailty syndrome and lymphocyte count was observed (P0.01). The concentration of IL-6 (P0.05), CRP (P0.05), and fibrinogen (P0.01) were significantly associated with frailty syndrome, but not of TNF-α, IL-beta, or IL-8. The severity of frailty syndrome was not dependent upon the clinical disease stage at diagnosis, the time elapsed since CaP diagnosis, the presence of metastases, or prostatectomy.Further research into the role of leukocyte subtypes and peripheral inflammation and the associated adverse outcomes in patients with CaP under ADT is warranted in order to tailor interventions aimed at reducing symptoms of frailty syndrome, such as loss of muscle strength and low physical activity.

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.