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Objective To develop a new composite disease activity score for gout and provide its first validation. Methods Disease activity has been defined as the ongoing presence of urate deposits that lead to acute arthritis and joint damage. Every measure for each Outcome Measures in Rheumatology core domain was considered. A 3-step approach (factor analysis, linear discriminant analysis, and linear regression) was applied to derive the Gout Activity Score (GAS). Decision to change treatment or 6-month flare count were used as the surrogate criteria of high disease activity. Baseline and 12-month followup data of 446 patients included in the Kick-Off of the Italian Network for Gout cohort were used. Construct- and criterion-related validity were tested. External validation on an independent sample is reported. Results Factor analysis identified 5 factors: patient-reported outcomes, joint examination, flares, tophi, and serum uric acid (sUA). Discriminant function analysis resulted in a correct classification of 79%. Linear regression analysis identified a first candidate GAS including 12-month flare count, sUA, visual analog scale (VAS) of pain, VAS global activity assessment, swollen and tender joint counts, and a cumulative measure of tophi. Alternative scores were also developed. The developed GAS demonstrated a good correlation with functional disability (criterion validity) and discrimination between patient- and physician-reported measures of active disease (construct validity). The results were reproduced in the external sample. Conclusion This study developed and validated a composite measure of disease activity in gout. Further testing is required to confirm its generalizability, responsiveness, and usefulness in assisting with clinical decisions.

Objective. Glomerulonephritis is a severe manifestation of systemic lupus erythematosus (SLE) that is usually treated with an extended course of intravenous (IV) cyclophosphamide (CYC). Given the side effects of this regimen, we evaluated the efficacy and the toxicity of a course of low-dose IV CYC prescribed as a remission-inducing treatment, followed by azathioprine (AZA) as a remission-maintaining treatment. Methods. In this multicenter, prospective clinical trial (the Euro-Lupus Nephritis Trial [ELNT]), we randomly assigned 90 SLE patients with proliferative glomerulonephritis to a high-dose IV CYC regimen (6 monthly pulses and 2 quarterly pulses; doses increased according to the white blood cell count nadir) or a low-dose IV CYC regimen (6 fortnightly pulses at a fixed dose of 500 mg), each of which was followed by AZA. Intent-to-treat analyses were performed. Results. Followup continued for a median of 41.3 months in the low-dose group and 41 months in the high-dose group. Sixteen percent of those in the low-dose group and 20% of those in the high-dose group experienced treatment failure (not statistically significant by Kaplan-Meier analysis). Levels of serum creatinine, albumin, C3, 24-hour urinary protein, and the disease activity scores significantly improved in both groups during the first year of followup. Renal remission was achieved in 71% of the low-dose group and 54% of the high-dose group (not statistically significant). Renal flares were noted in 27% of the low-dose group and 29% of the high-dose group. Although episodes of severe infection were more than twice as frequent in the high-dose group, the difference was not statistically significant. Conclusion. The data from the ELNT indicate that in European SLE patients with proliferative lupus nephritis, a remission-inducing regimen of low-dose IV CYC (cumulative dose 3 gm) followed by AZA achieves clinical results comparable to those obtained with a high-dose regimen

Several single nucleotide polymorphisms (SNPs) have been associated with rheumatoid arthritis (RA) such as peptidylarginine deiminase-4 (PADI4), osteopontin (OPN), and perforin (PRF1) genes. Thus, we aimed at analysing the influence of eight SNPs in these candidate genes on RA susceptibility and their association with laboratory and clinical features in terms of response to anti-TNF therapy.We performed a case-control study on 377 Caucasian RA patients and 391 healthy, ethnicity-matched, population-based controls. All subjects were genotyped for PADI4_89/94, PADI4_92, PADI4_104, PADI4_100 in PADI4; -156G/GG and +1239A/C in OPN and A91V and N252S in PRF1 genes. The patients were stratified for shared epitope (SE) HLA-DRB1. rheumatoid factor (RF) and anti-citrullinated protein/peptide antibodies (ACPA) were analysed. The patients started anti-TNF treatment and they were evaluated at baseline and after 12 weeks. Disease activity was evaluated with DAS28 and response to treatment with EULAR criteria.A statistically significant association between RA and OPN -156G/GG was found (p=0.023). SE was firmly confirmed to be associated with RA (OR=3.68; p10-10). No other statistically significant association with clinical and laboratory features were observed.For the first time, in an Italian cohort, we report the association between -156G/GG in OPN gene and RA susceptibility. Short-term response to anti-TNF therapy was not influenced by the genetic variants studied.

It has been postulated that host factors, such as the human leucocyte antigen (HLA) system, may play a predominant role in the pathogenesis of HCV-related extra-hepatic manifestations. This study was performed to investigate the role of HLA- DR and DQ alleles in a group of Italian patients, with HCV infection and associated extrahepatic manifestations and to test whether an association between HCV genotype, HLA locus and clinical or serological manifestations can be demonstrated. Thirty unrelated patients affected by HCV infection with extra-hepatic manifestations were consecutively included in the study. One hundred and sixty-three HCV patients without extrahepatic manifestations were tested as controls for the prevalence of HCV genotypes, and 283 healthy donors were used as controls for HLA class II alleles distribution. HCV-RNA was quantified by an reverse transcription-PCR. HLA class II alleles typing was performed using a standard microlymphocytotoxicity assay on B lymphocyte purified. HCV 2c genotype was found in 53.3% compared to 18.4% of controls (p=0.00001; OR=5.1). Cryoglobulins were detected in 72.7% DR6+ patients and in 31.6% DR6- patients (p=0.05; OR=3.21). Rheumatoid factor was found in 90.9% of DR6+ patients and in 42.1% DR6- patients (p=0.018; OR 13.7). Only two DR5+ patients (20%) had cryoglobulinemia, while 6 patients (30%) in the DR5- group had cryoglobulinemia (p=0.02; OR=0.07). Associations were found between DR7 and ANA (OR=1.74) and between DQ2 and ANA (OR=1.97). According to our findings HLA-DR6 might play an important role in developing extra-hepatic manifestations and genotype 2c could be considered as a risk factor for their onset.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of autoantibodies against intracellular components, the formation of immune complexes, and inflammation in various organs, typically the skin and kidney glomeruli. The etiology of the disease is not well understood but is most likely the result of the interaction between genetic and environmental factors. In order to identify susceptibility loci for SLE, we have performed genome scans with microsatellite markers covering the whole genome in families from Argentina, Italy, and Europe. The results reveal a heterogeneous disease with different susceptibility loci in different family sets. We have found significant linkage to chromosome 17p12-q11 in the Argentine set of families. The maximum LOD score was given by marker D17S1294 in combination with D17S1293, when assuming a dominant inheritance model (Z = 3.88). We also analyzed a repeat in the promoter region of the NOS2A gene, a strong candidate gene in the region, but no association was found. The locus on chromosome 17 has previously been identified in genetic studies of multiple sclerosis families. Several other interesting regions were found at 1p35, 1q31, 3q26, 5p15, 11q23 and 19q13, confirming previously identified loci for SLE or other autoimmune diseases.

Objectives: To determine whether highly active antiretroviral therapy (HAART) is effective in HIV-associated neurocognitive impairment. Design: An open label, prospective, observational study. Methods: Since April 1996, 116 patients with advanced HIV infection, reverse transcriptase inhibitor (nRTI) experienced but protease inhibitor (PI) naive, were screened for the presence of neurocognitive impairment. Ninety patients with confounding neurological illness, opportunistic infections or drug abuse were excluded. The remaining 26 patients underwent comprehensive neuropsychological testing, and laboratory measures before, after 6 and after 15 months of treatment with one PI plus two nRTI. Results: The prevalence of neurocognitive impairment decreased from 80.8% (baseline) to 50.0% (P < 0.05) (sixth month) and to 21.7% (P < 0.001) (15th month). Among the functions explored, the impairment of concentration and speed of mental processing decreased from 65.4 to 21.7% (P < 0.01) and of memory impairment from 50 to 8.7% (P < 0.01). Comparing baseline with the sixth and 15th month raw scores, a statistically significant improvement was seen in measures exploring concentration and speed of mental processing (P < 0.05), mental flexibility (P < 0.05), memory (P < 0.05), fine motor functions (P < 0.05) and visuospatial and constructional abilities (P < 0.01). After 6 months of HAART patients with a normal neuropsychological examination had lower mean plasma viraemia (2.95 versus 3.97 log copies/ml, P < 0.05) and greater mean log plasma HIV RNA changes from baseline (-1.84 versus -0.83 log copies/ml, P < 0.05) than neuropsychologically impaired subjects. Conclusion: HAART produces a positive and sustained effect on neurocognitive impairment in HIV-infected patients. A reduction of plasma viral load was associated with the regression of neuropsychological test abnormalities.

Introduction: Gout is the most prevalent arthritis and significantly impacts on function and quality of life. Given that gout associates with disabling comorbid conditions, it is not clear whether such a complex of diseases accounts for the increased disability or if gout may play a role by itself. This study aims to evaluate the specific influence of gout and disease-related features on functional disability and health-related quality of life (HRQoL) in patients with gout followed in rheumatology clinics.Methods: A random sample of patients was drawn from clinical registries of 30 rheumatology clinics across Italy. Sociodemographic, general health and gout-specific variables were collected. Functional disability and HRQoL were assessed by the health assessment questionnaire (HAQ) and the Physical and Mental Component Summary scores (PCS and MCS) of the Short Form-36 (SF-36). Crude and adjusted ordinal logistic and linear regression models were applied to investigate the specific contribution of different variables on HAQ and SF-36 scores. Results are presented as odds ratio (OR) or mean difference (MD) and 95% confidence intervals.Results: Out of 446 patients with gout, 90% were males with a mean age of 63.9 years and median disease duration of 3.8 years; the majority of patients were overweight or obese, and with several comorbidities; 21.1% showed at least moderate disability; the PCS score was significantly lower than expected age- and gender-matched samples in the general population, while MCS score was not. After adjusting for potential sociodemographic and general-health confounders, gout-specific variables significantly impacted on HAQ, including polyarticular involvement OR 3.82 (1.63, 8.95), presence of tophi OR 1.92 (1.07, 3.43) and recent attacks OR 2.20 (1.27, 3.81). Consistent results were found for PCS. The impairment of PCS compared to the general population was limited to patients with features of chronic gout. MCS was only affected by recent attacks (MD -2.72 [-4.58, -0.86]) and corticosteroid treatment (-3.39 [-5.30,-1.48]).Conclusions: The data from the KING study confirm that gout impacts on disability and provide evidence for an independent association of gout and gout-related features with functional outcome and HRQoL. This result supports the need to improve specific treatment in gout.

Antineutrophil cytoplasmic antibodies (ANCA) are present in several vasculitides and in other immunomediated diseases. The reported prevalence of ANCA in rheumatoid arthritis (RA) is variable. In addition, the presence of such autoantibodies has been poorly investigated in synovial fluid (SF). The objectives of this study were (1) to investigate the presence of ANCA both in the serum and in SF from patients with RA and other forms of synovitis (OS); (2) to analyze the reactivity of ANCA against isolated antigens proteinase 3 (PR3), myeloperoxidase (MPO) and lactoferrin (LF); and (3) to evaluate the clinical relevance of these autoantibodies.Twenty-eight patients with RA, 13 with OS, and 17 with osteoarthritis (OA) of the knee joint were studied. No patient had clinical manifestations of vasculitis. SF and serum samples were investigated for the presence of ANCA by indirect immunofluorescence (IIF); the reactivity against PR3, MPO and LF was assessed by ELISA.ANCA were detected by IIF in SF of 39.3% patients with RA, 38.5% with OS, and 5.9% with OA. With 2 exceptions, patients who had ANCA in SF showed positivity also in serum. The presence of both anti-MPO and anti-LF antibodies was found in 3 patients with RA and 1 with OA; a patient with RA showed antibodies only against LF and another one with RA only against MPO. No reactivity was found against PR3. In patients with RA ANCA were not associated with disease activity.We found an increased incidence of ANCA both in SF and serum from patients with RA and OS. The pathogenic role and the clinical relevance of such autoantibodies in these diseases remain to be established.

Patients affected by AIDS-related complex (ARC) show several immunological abnormalities which may lead to a disregulation of immunosurveillance against viral latent infections. In this paper evidence for Epstein-Barr virus (EBV) reactivation in seven out of eight affected by persistent generalized lymphadenopathy is given. These patients showed either elevated levels of circulating EBNA-positive transformed cells or depressed EBV-specific T cell cytotoxicity, as assessed by the regression assay, or both. A direct involvement of EBV in the pathogenesis of ARC is thus suggested. Natural killer cell activity was found decreased, correlating to the evidence of circulating EBV-infected cells and of impaired EBV-specific immune control. These data provide evidence that, when specific immune mechanisms lose control on ubiquitous latent viruses, the risk for reactivation becomes higher. In the case of EBV, direct evidence of this event is provided by the emergence in the peripheral blood of clones of infected cells with unlimited growth potential.

Axial spondyloarthritides (axSpA) are a group of disorders that share similar pathogenetic mechanisms and clinical picture. The aim of this retrospective multicentric study was to evaluate demographic and clinical differences between ankylosing spondylitis (AS) and non-radiographic axSpA (nr-axSpA) patients.Patients from 7 rheumatological centres in the Lazio region of Italy were included from January 1st, 2010 to April 1st, 2018, if they had undergone pelvic and/or spine radiographs or magnetic resonance imaging (MRI). Images were evaluated by one experienced radiologist in each centre who already had the clinical suspicion of axSpA. Clinical and therapeutic data were collected at the last observation visit. Categorical variables were presented with percentages and analysed by Chi squared test. Continuous variables were expressed as mean ± standard deviation and compared using the parametric unpaired t-test or the non-parametric Mann-Whitney U-test, when appropriate. p-values0.05 were considered significant.210 axSpA patients were included: 65.2% with AS and 34.7% with nr-axSpA. When comparing the two groups, AS patients had longer disease duration, were older, were more frequently males, had a greater diagnostic delay and a higher body mass index than the nr-axSpA patients (p0.0001, p0.0001, p=0.003 p=0.007, and p=0.04, respectively). The peripheral joints of the nr-axSpA patients were more frequently involved, had higher frequency of inflammatory bowel disease, higher C-reactive protein levels and lower frequency of HLA-B27 positivity (p=0.005, p=0.007, p=0.01, and p=0.01, respectively). TNF inhibitors were used in 87.8% patients with AS and 78.3% with nr-axSpA (p=0.04). More fat metaplasia was observed on MRI in the nr-axSpA group than in the AS group at sacroiliac joints (p=0.003), and more backfills were detected in the AS group on spine-MRI (p=0.003). Spine-bone marrow oedema was more prevalent in AS than in nr-axSpA (p=0.04), and more sclerosis and backfill were found in AS (p=0.003 and p=0.01, respectively).In clinical practice, distinctive features in AS and nr-axSpA patients emerged. Imaging is crucial in guiding the choice of treatment in order to control disease activity and inflammation.

ObjectiveThere is still a great deal to learn about the influence of sex in systemic sclerosis (SSc). In this respect, national registries provide large and homogeneous patient cohorts for analytical studies. We therefore investigated a wide-ranging and well-characterized SSc series with the aim of identifying sex differences in disease expression, with a special focus on demographic, clinical, and serological characteristics.MethodsA multicenter SSc cohort of 2281 patients, including 247 men, was recruited in the Italian Systemic sclerosis PRogression INvestiGation (SPRING) registry. Demographic data, disease manifestations, serological profile, and internal organ involvement were compared.ResultsThe overall female/male ratio was 8.2:1. Female/male ratios for limited cutaneous SSc, diffuse cutaneous SSc, and SSc sine scleroderma subsets were 8.7:1, 4.9:1, and 10.7:1, respectively. A shorter time from onset of Raynaud phenomenon to SSc diagnosis, an increased prevalence of the diffuse cutaneous subset, renal crisis, and digital ulcers were found in males, whereas a significantly higher percentage of sicca syndrome, serum antinuclear antibodies, antiextractable nuclear antigens, anti-La/SSB, and anticentromere protein B was detected in the female group. Males exhibited lower left ventricular ejection fraction, as well as higher prevalence of conduction blocks, arrhythmias, ground glass, and honeycombing. Moreover, forced vital capacity and total lung capacity were medially lower in men than in women. Finally, males were more frequently treated with immunosuppressive drugs.ConclusionOur study further supports the presence of several sex-related differences in patients with SSc. These differences were pronounced in the severity of cutaneous, peripheral vascular, and cardiopulmonary involvement for male patients, whereas an increased prevalence of sicca syndrome and a specific autoantibody profile characterized the female sex.

© 2019 Elsevier Ltd. All rights reserved., Background: Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods: In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings: Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation: Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes.

After the first successful pregnancy in a liver transplant recipient in 1978, much evidence has accumulated on the course, outcomes and management strategies of pregnancy following liver transplantation. Generally, liver transplantation restores sexual function and fertility as early as a few months after transplant. Considering that one third of all liver transplant recipients are women, that approximately one-third of them are of reproductive age (18-49 years), and that 15% of female liver transplant recipients are paediatric patients who have a >70% probability of reaching reproductive age, the issue of pregnancy after liver transplantation is rather relevant, and obstetricians, paediatricians, and transplant hepatologists ever more frequently encounter such patients. Pregnancy outcomes for both the mother and infant in liver transplant recipients are generally good, but there is an increased incidence of preterm delivery, hypertension/preeclampsia, foetal growth restriction, and gestational diabetes, which, by definition, render pregnancy in liver transplant recipients a high-risk one. In contrast, the risk of congenital anomalies and the live birth rate are comparable to those of the general population. Currently there are still no robust guidelines on the management of pregnancies after liver transplantation. The aim of this position paper is to review the available evidence on pregnancy in liver transplant recipients and to provide national Italian recommendations for clinicians caring for these patients. (C) 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Objective: The optimal choice of a second biological disease-modifying anti-rheumatic drug (bDMARD) after failure with first line tumour necrosis factor inhibitor (TNFi) represents a critical therapeutic challenge. This study aims to evaluate the persistence with treatment using second line bDMARDs with different mechanisms of action in rheumatoid arthritis (RA) patients with inadequate response to first line TNFi. Method: A retrospective cohort study on administrative healthcare databases was conducted. We analysed the relationship between different bDMARDs and persistence with treatment in RA patients who started second line bDMARD therapy according to two different strategies: cycling (second TNFi) or switching [change in mechanism of action: abatacept (ABA), tocilizumab (TCZ), and rituximab (RTX)] with or without concomitant conventional synthetic (cs) DMARDs. Results: The cohort comprised 1434 patients. The mean age was 53.8years and 1142 (79.6%) were women. Among second line bDMARDs, 969 patients (67.6%) started TNFi, 204 (14.2%) ABA, 145 (10.1%) RTX, and 116 (8.1%) TCZ. A bDMARD was prescribed as monotherapy in 359 patients (25.0%). The switching strategy showed a lower overall discontinuation rate [hazard ratio (HR) 0.72], while switching compared to cycling showed significantly better survival for ABA (HR 0.61) and RTX (HR 0.76), but no significant difference for TCZ (HR 0.82). A lower impact of better drug survival in the switching strategy occurred in patients with concurrent methotrexate. Conclusions: Among RA patients failing a first TNFi, switching is associated with marginally better persistence, in particular for ABA and RTX, with only marginal differences in patients on concurrent csDMARDs.

© Copyright Clinical and Experimental Rheumatology 2022., Objectives: To define the clinical spectrum time-course and prognosis of non-Asian patients positive for anti-MDA5 antibodies. Methods: We conducted a multicentre, international, retrospective cohort study. Results: 149 anti-MDA5 positive patients (median onset age 53 years, median disease duration 18 months), mainly females (100, 67%), were included. Dermatomyositis (64, 43%) and amyopathic dermatomyositis (47, 31%), were the main diagnosis; 15 patients (10%) were classified as interstitial pneumonia with autoimmune features (IPAF) and 7 (5%) as rheumatoid arthritis. The main clinical findings observed were myositis (84, 56%), interstitial lung disease (ILD) (108, 78%), skin lesions (111, 74%), and arthritis (76, 51%). The onset of these manifestations was not concomitant in 74 cases (50%). Of note, 32 (21.5%) patients were admitted to the intensive care unit for rapidly progressive-ILD, which occurred in median 2 months from lung involvement detection, in the majority of cases (28, 19%) despite previous immunosuppressive treatment. One-third of patients (47, 32% each) was ANA and anti-ENA antibodies negative and a similar percentage was anti-Ro52 kDa antibodies positive. Non-specific interstitial pneumonia (65, 60%), organising pneumonia (23, 21%), and usual interstitial pneumonia-like pattern (14, 13%) were the main ILD patterns observed. Twenty-six patients died (17%), 19 (13%) had a rapidly progressive-ILD. Conclusions: The clinical spectrum of the anti-MDA5 antibodies-related disease is heterogeneous. Rapidly-progressive ILD deeply impacts the prognosis also in non-Asian patients, occurring early during the disease course. Anti-MDA5 antibody positivity should be considered even when baseline autoimmune screening is negative, anti-Ro52 kDa antibodies are positive, and radiology findings show a NSIP pattern.

Objective To investigate differences in coronavirus disease 2019 (COVID-19) mortality between patients with rheumatic musculoskeletal diseases (RMD) and the general population in Italy. Methods We analysed the data from the national surveillance study promoted by the Italian Society for Rheumatology (CONTROL-19 database) including patients with RMD and COVID-19 between 26 March 2020 and 29 November 2020, compared with official data from the Italian population (within the same period) adjusted for age, sex and geographic location. The main outcome of the analyses was mortality. The relationship between RMD and mortality was analysed using adjusted logistic models and sensitivity analyses were conducted to support the robustness of our results. Results We included 668 RMD patients (62.7% with inflammatory arthritis, 28.6% with systemic autoimmune diseases), who had a mean age of 58.4 years and of which 66% were female. Compared to the general population, the RMD population showed an increased risk of death (OR 3.10 (95% CI 2.29–4.12)), independently from the differences in age and sex distribution. Even after considering the potential influence of surveillance bias, the OR was 2.08 (95% CI: 1.55–2.73). Such excess of risk was more evident in the subgroup of younger patients, and more consistent in women. Subjects with systemic autoimmune diseases showed a higher risk of death than patients with any other RMDs. Conclusions Patients with RMD and COVID-19 infection evidenced a significant increase in mortality during the first pandemic phases in Italy. These findings support the need for strong SARS-CoV-2 prevention in patients with rheumatic diseases.

ObjectivesExcess risk of suicide has been reported among workers in agriculture, fishery, forestry and hunting (AFFH). However, there is still uncertainty in the quantification of the risk and in the contribution of work-related factors. We aimed to quantify the suicide mortality risk among these workers in Italy.MethodsWe carried out a historical cohort study based on record linkage between the 2011 Italian census and the mortality archives for years 2012–2017. The mortality rate ratio (MRR) was used as a measure of risk. MRR was estimated through quasi-Poisson regression models using workers in other sectors as reference category. Models were adjusted for age, citizenship, marital status, area of residence, education, employment status and hours worked per week.ResultsThe cohort included 1 004 655 workers employed in the AFFH sector and 15 269 181 workers in other sectors. During the 6-year follow-up, 559 deaths from suicide (500 men and 59 women) occurred among AFFH workers and 5917 (4935 men and 982 women) among workers in other sectors. The MRR for suicide was 1.36 (95% CI 1.19 to 1.55) among men and 1.18 (95% CI 0.87 to 1.60) among women. The excess risk was remarkably high for casual and fixed-term contract workers (3.01, 95% CI 1.50 to 6.04).ConclusionsMale workers in AFFH are at high risk of suicide mortality, and casual and fixed-term contract workers are at exceedingly high risk. Our study also suggests a higher risk among single, highly educated and long-hours workers. Female workers in AFFH do not have an appreciably increased risk.

BackgroundItaly was one of the first countries significantly affected by the coronavirus disease 2019 (COVID-19) epidemic. The Italian Society for Rheumatology promptly launched a retrospective and anonymised data collection to monitor COVID-19 in patients with rheumatic and musculoskeletal diseases (RMDs), the CONTROL-19 surveillance database, which is part of the COVID-19 Global Rheumatology Alliance.MethodsCONTROL-19 includes patients with RMDs and proven severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) updated until May 3rd 2020. In this analysis, only molecular diagnoses were included. The data collection covered demographic data, medical history (general and RMD-related), treatments and COVID-19 related features, treatments, and outcome. In this paper,we report the first descriptive data from the CONTROL-19 registry.ResultsThe population of the first 232 patients (36% males) consisted mainly of elderly patients (mean age 62.2 years), who used corticosteroids (51.7%), and suffered from multi-morbidity (median comorbidities 2). Rheumatoid arthritis was the most frequent disease (34.1%), followed by spondyloarthritis (26.3%), connective tissue disease (21.1%) and vasculitis (11.2%). Most cases had an active disease (69.4%). Clinicalpresentationof COVID-19 was typical, with systemic symptoms (fever and asthenia)and respiratorysymptoms. The overall outcome was severe, with high frequencies of hospitalisation (69.8%), respiratorysupport oxygen (55.7%), non-invasive ventilation (20.9%) or mechanical ventilation (7.5%), and 19% of deaths. Male patients typically manifested a worse prognosis. Immunomodulatory treatments were not significantlyassociatedwith an increasedrisk of intensive care unit admission/mechanicalventilation! death.ConclusionAlthough the reportmainly includes the most severe cases, its temporal and spatial trend supports the validity of the nationalsurveillance system. More complete data are being acquired in order to both test the hypothesis thatRMD patients may have a different outcome from that of the generalpopulation and determine the safety of immunomodulatory treatments.

Objective To investigate risk factors for damage development in a prospective inception cohort of early diagnosed SLE patients. Methods The Early Lupus Project recruited an inception cohort of patients within 12 months of SLE classification (1997 ACR criteria). At enrolment and every 6 months thereafter, the SLICC/ACR Damage Index was recorded. The contribution of baseline and time-varying covariates to the development of damage, defined as any SLICC/ACR Damage Index increase from 0 to ≥1, was assessed using univariate analysis. Forward-backward Cox regression models were fitted with covariates with P Results Overall, 230 patients with a mean (s.d.) age of 36.5 (14.4) years were eligible for this study; the mean number of visits per patient was 5.3 (2.7). There were 51 (22.2%) patients with SLICC/ACR Damage Index ≥1 after 12 months, 59 (25.6%) after 24 months and 67 (29.1%) after 36 months. Dyslipidaemia [P = 0.001; hazard ratio (HR) 2.9; 95% CI 1.5, 5.6], older age (P = 0.001; HR 3.0; 95% CI 1.6, 5.5), number of organs/systems involved (P = 0.002; HR 1.4; 95% CI 1.1, 1.8) and cardiorespiratory involvement (P = 0.041; HR 1.9; 95% CI 1.0, 3.7) were independently associated with an increased risk of developing damage. Risk profiles for damage development differed for glucocorticoid-related and -unrelated damage. HCQ use (P = 0.005; HR 0.4; 95% CI 0.2, 0.8) reduced the risk of glucocorticoid-unrelated damage. Conclusion We identified risk factors of damage development, but little effect of glucocorticoids, in this early SLE cohort. Addressing modifiable risk factors from the time of SLE diagnosis might improve patient outcomes.

Objectives: Current guidelines recommend use of a diagnostic algorithm to assess disease severity in cases of suspected nonalcoholic fatty liver disease (NAFLD). We applied this algorithm to HIV-monoinfected patients. Methods: We analysed three prospective screening programmes for NAFLD carried out in the following cohorts: the Liver Disease in HIV (LIVEHIV) cohort in Montreal, the Modena HIV Metabolic Clinic (MHMC) cohort and the Liver Pathologies in HIV in Palermo (LHivPa) cohort. In the LIVEHIV and LHivPa cohorts, NAFLD was diagnosed if the controlled attenuation parameter (CAP) was ≥248dB/m; in the MHMC cohort, it was diagnosed if the liver/spleen Hounsfield unit (HU) ratio on abdominal computerized tomography scan was

Background: Large, representative studies are needed to evaluate cause-specific aspects of socio-economic inequalities in mortality. Methods: We conducted a census-based retrospective cohort study to quantify differences in cause-specific premature mortality by educational level in Italy. We linked the 2011 Italian census with 2012 and 2013 death registries. We used the mortality rate ratio (MRR) as a measure of relative inequality. Results: Overall, 305 043 deaths (190 061 men 114982 women) were registered from a population of 35 708 445 subjects aged 30-74. The age-standardized mortality rate for all educational levels was 57.68 deaths per 10 000 personyears among men and 31.41 among women. MRR from all causes was 0.51 (95% CI: 0.49; 0.52) in men and 0.63 (95% CI: 0.61; 0.65) in women for the highest (university) compared to the lowest level of education (none or primary school). The association was stronger in single than in married individuals: MRRs were 0.36 (95% CI: 0.34; 0.39) in single men, 0.57 (95% CI: 0.55; 0.59) in married men, 0.44 (95% CI: 0.40; 0.47) in single women and 0.69 (95% CI: 0.66; 0.72) in married women. High education was associated with lower mortality from liver, circulatory, chronic respiratory and genitourinary diseases in both sexes. Highly educated men had a lower mortality from lung cancer than less educated men, whereas highly educated women did not have a reduced mortality from lung and breast cancers. Conclusion: Level of education is a strong indicator of premature mortality. The magnitude of the association between educational level and mortality differs across sexes, marital status and causes of death. © 2018 The Author(s) 2018. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.

Pregnancy requires a special management in women with inflammatory rheumatic diseases (RDs), with the aim of controlling maternal disease activity and avoiding fetal complications. Despite the heterogeneous course of RDs during pregnancy, their impact on pregnancy largely relates to the extent of active inflammation at the time of conception. Therefore, accurate evaluation of disease activity is crucial for the best management of pregnant patients. Nevertheless, there are limitations in using conventional measures of disease activity in pregnancy, as some items included in these instruments can be biased by symptoms or by physiological changes related to pregnancy and the pregnancy itself may influence laboratory parameters used to assess disease activity. This article aims to summarize the current literature about the available instruments to measure disease activity during pregnancy in RDs. Systemic lupus erythematosus is the only disease with instruments that have been modified to account for several adaptations which might interfere with the attribution of signs or symptoms to disease activity during pregnancy. No modified-pregnancy indices exist for women affected by other RDs, but standard indices have been applied to pregnant patients. The current body of knowledge shows that the physiologic changes that occur during pregnancy need to be either adapted from existing instruments or developed to improve the management of pregnant women with RDs. Standardized instruments to assess disease activity during pregnancy would be helpful not only for clinical practice but also for research purposes. info:eu-repo/semantics/publishedVersion

Objective To describe the clinical and serological features of a prospectively followed cohort of early diagnosed systemic lupus erythematosus (SLE) patients during a one-year follow-up period. Methods SLE patients with disease duration less than 12 months were consecutively enrolled in a multicentre, prospective study. At study entry and then every 6 months, a large panel of data was recorded. Results Of 260 patients enrolled, 185 had at least 12 months of follow-up; of these, 84.3% were female, 92.4% were Caucasians. Mean diagnostic delay was about 20 months; higher values of European Consensus Lupus Activity Measurement (ECLAM) and of organs/systems involved were both associated with shorter diagnostic delay. Clinical and serological parameters improved after study entry. However, patients' quality of life deteriorated and cardiovascular risk factors significantly increased. About one-third of patients with active disease at study entry went into remission (ECLAM = 0). Negative predictors for remission were: oral ulcers, arthritis, low C4, anti-SSB (Ro) antibodies and therapy with mycophenolate. There was a widespread use of glucocorticoids both at baseline and during follow-up. Conclusion Clinical symptoms and serological parameters improve during the first period after diagnosis. However, patients’ quality of life deteriorates. The widespread use of glucocorticoids is probably the reason for the early significant increase of some cardiovascular risk factors.

Objective To evaluate if the timing of appearance with respect to disease onset may influence the arthritis presentation pattern in antisynthetase syndrome (ASSD). Methods The patients were selected from a retrospective large international cohort of ASSD patients regularly followed-up in centres referring to AENEAS collaborative group. Patients were eligible if they had an antisynthetase antibody testing positive in at least two determinations along with arthritis occurring either at ASSD onset (Group 1) or during the course of the disease (Group 2). Results 445 (70%; 334 females, 110 males, 1 transsexual) out of the 636 ASSD we collected had arthritis, in the majority of cases (367, 83%) from disease onset (Group 1). Patients belonging to Group 1 with respect to Group 2 had an arthritis more commonly polyarticular and symmetrical (p=0.015), IgM-Rheumatoid factor positive (p=0.035), erosions at hands and feet plain x-rays (p=0.036) and more commonly satisfying the 1987 revised classification criteria for rheumatoid arthritis (RA) (p=0.004). Features such as Raynaud's phenomenon, mechanic's hands and fever (e.g. accompanying findings) were more frequently reported in Group 2 (p=0.005). Conclusion In ASSD, the timing of appearance with respect to disease onset influences arthritis characteristics. In particular, RA features are more common when arthritis occurs from ASSD onset, suggesting an overlap between RA and ASSD in these patients. When arthritis appears during the follow-up, it is very close to a connective tissue disease-related arthritis. Also, the different prevalence of accompanying features between these two groups is in line with this possibility

Purpose: Large studies are needed to evaluate socioeconomic inequality for site-specific cancer mortality. We conducted a longitudinal census-based national study to quantify the relative inequality in cancer mortality among educational levels in Italy. Methods: We linked the 2011 Italian census with the 2012 and 2013 death registries. Educational inequality in overall cancer and site-specific cancer mortality were evaluated by computing the mortality rate ratio (MRR). Results: A total of 35,708,445 subjects aged 30–74 years and 147,981 cancer deaths were registered. Compared to the lowest level of education (none or primary school), the MRR for all cancers in the highest level (university) was 0.57 (95% CI 0.55; 0.58) in men and 0.84 (95% CI 0.81; 0.87) in women. Higher education was associated with reduced risk of mortality from lip, oral cavity, pharynx, oesophagus, stomach, colon and liver in both sexes. Higher education (university) was associated with decreased risk of lung cancer in men (MRR: 0.43, 95% CI 0.41; 0.46), but not in women (MRR: 1.00, 95% CI 0.92; 1.10). Highly educated women had a reduced risk of mortality from cervical cancer than lower educated women (MRR: 0.39, 95% CI 0.27; 0.56), but they had a similar risk for breast cancer (MRR: 1.01, 95% CI 0.94; 1.09). Conclusions: Education is inversely associated with total cancer mortality, and the association was stronger in men. Different patterns and trends in tobacco smoking in men and women account for at least most of the gender differences. © 2017, Springer International Publishing AG.

The staging of liver fibrosis is pivotal for defining the prognosis and indications for therapy in hepatitis C. Although liver biopsy remains the gold standard, several noninvasive methods are under evaluation for clinical use. The aim of this study was to validate the recently described sequential algorithm for fibrosis evaluation (SAFE) biopsy, which detects significant fibrosis (≥F2 by METAVIR) and cirrhosis (F4) by combining the AST-to-platelet ratio index and Fibrotest-Fibrosure, thereby limiting liver biopsy to cases not adequately classifiable by noninvasive markers. Hepatitis C virus (HCV) patients (2035) were enrolled in nine locations in Europe and the United States. The diagnostic accuracy of SAFE biopsy versus histology, which is the gold standard, was investigated. The reduction in the need for liver biopsies achieved with SAFE biopsy was also assessed. SAFE biopsy identified significant fibrosis with 90.1% accuracy (area under the receiver operating characteristic curve = 0.89; 95% confidence interval, 0.87-0.90) and reduced by 46.5% the number of liver biopsies needed. SAFE biopsy had 92.5% accuracy (area under the receiver operating characteristic curve = 0.92; 95% confidence interval, 0.89-0.94) for the detection of cirrhosis, obviating 81.5% of liver biopsies. A third algorithm identified significant fibrosis and cirrhosis simultaneously with high accuracy and a 36% reduction in the need for liver biopsy. The patient's age and body mass index influenced the performance of SAFE biopsy, which was improved with adjusted Fibrotest-Fibrosure cutoffs. Two hundred two cases (9.9%) had discordant results for significant fibrosis with SAFE biopsy versus histology, whereas 153 cases (7.5%) were discordant for cirrhosis detection; 71 of the former cases and 56 of the latter cases had a Fibroscan measurement within 2 months of histological evaluation. Fibroscan confirmed SAFE biopsy findings in 83.1% and 75%, respectively. Conclusion: SAFE biopsy is a rational and validated method for staging liver fibrosis in hepatitis C with a marked reduction in the need for liver biopsy. It is an attractive tool for large-scale screening of HCV carriers. (HEPATOLOGY 2009.)

Objective:To update the follow-up of the Euro-Lupus Nephritis Trial (ELNT), a randomised prospective trial comparing low-dose (LD) and high-dose (HD) intravenous (IV) cyclophosphamide (CY) followed by azathioprine (AZA) as treatment for proliferative lupus nephritis.Patients and methods:Data for survival and kidney function were prospectively collected during a 10-year period for the 90 patients randomised in the ELNT, except in 6 lost to follow-up.Results:Death, sustained doubling of serum creatinine and end-stage renal disease rates did not differ between the LD and HD group (5/44 (11%) vs 2/46 (4%), 6/44 (14%) vs 5/46 (11%) and 2/44 (5%) vs 4/46 (9%), respectively) nor did mean serum creatinine, 24 h proteinuria and damage score at last follow-up. Most patients in both groups were still treated with glucocorticoids, other immunosuppressant agents and blood pressure lowering drugs. After 10 years of follow-up, the positive predictive value for a good outcome of an early drop in proteinuria in response to initial immunosuppressive therapy was confirmed.Conclusion:The data confirm that a LD IVCY regimen followed by AZA—the “Euro-Lupus regimen”—achieves good clinical results in the very long term.

Background/Aims: Around 15-25% of chronic hepatitis C patients treated with Peg-IFN plus ribavirin become HCV-RNA negative by PCR during therapy but relapse after its withdrawal. We investigated whether minimal residual viremia (MRV) might be detected in these cases by Transcription-Mediated Amplification (TMA). Methods: Two hundred and ninety-two consecutive patients (143 HCV-1, 82 HCV-2, 56 HCV-3 and 11 HCV-4) were prospectively treated with a standard schedule of Peg-IFNα 2b plus ribavirin combination and end-of-therapy response was assessed by conventional PCR using 2 protocol serum samples obtained 6-8 h before the last two scheduled weekly injections of Peg-IFN. PCR negative samples were re-tested by TMA and the results were then correlated with the virological outcome after therapy withdrawal. Results: Among 208 patients who were repeatedly HCV-RNA negative by PCR at the end-of-therapy, 26 (12.5%) were found HCV-RNA positive by TMA. Twenty-two of them, (96%) were PCR-relapsers after therapy withdrawal, compared to only 14% of the 182 TMA negative patients (P

Objectives Staging liver fibrosis in chronic viral hepatitis C (HCV) patients is essential for prompting surveillance and treatment. The aim of this study was to develop a nomogram, on the basis of simple clinical and laboratory variables, to predict three clinically significant stages of fibrosis (nil-mild, moderate, advanced/cirrhosis), using histology as reference, and to compare its performance with that of FibroTest, a widely used noninvasive fibrosis score. Materials and methods Nomograms are graphical representations of a mathematical formula, used as predictive tools. The study retrospectively recruited 406 HCV patients undergoing liver biopsy. Nomogram was developed in a training set of 252 patients and tested in a validation set of 154 patients. Histology was staged according to the Metavir system. Fibrosis stages were subgrouped as follows: advanced fibrosis/cirrhosis (F3/F4, 24%), nil-mild (F0/F1, 36%), and moderate (F2, 40%). Age at biopsy, aspartate aminotransferase, γ-glutamyl transpeptidase, albumin, platelet count, and prothrombin activity formed the basis for the so-called Fibro-Nomogram, which, in one graphical representation, estimates probability for different stages of fibrosis. Results Areas under the receiver-operating characteristic curves for advanced fibrosis/cirrhosis were similar for training (0.86) and validation sets (0.87). For nil-mild fibrosis, area under the receiver-operating characteristics were 0.81 and 0.79. Compared with FibroTest, Fibro-Nomogram performed slightly better at predicting severe fibrosis (F3/F4) with positive likelihood ratio (LR+) 5.07 (95% confidence interval 3.08-8.37) versus LR+ 3.82 (95% confidence interval 2.56-5.71) for FibroTest. For nil-mild fibrosis, the two tests showed limited but comparable performances. Conclusion In HCV patients, Fibro-Nomogram, an inexpensive and readily available predictive tool, could enable clinicians to interpret patients' profile, concurrently stratifying patients into three clinically relevant probability categories with good overall performance.

Human type 1 diabetes (T1D) is an autoimmune disease associated with major histocompatibility complex polymorphisms, β-cell autoantibodies, and autoreactive T cells. However, there is increasing evidence that innate cells may also play critical roles in T1D. We aimed to monitor peripheral immune cells in early stages of T1D (i.e., in healthy autoantibody-positive subjects) and in more advanced phases of the disease (i.e., at disease onset and years after diagnosis). We found a mild but significant and reproducible peripheral neutropenia that both precedes and accompanies the onset of T1D. This reduction was not due to peripheral neutrophil cell death, impaired differentiation, or the presence of anti-neutrophil antibodies. Neutrophils were observed by electron microscopy and immunohistochemical analysis in the exocrine pancreas of multiorgan donors with T1D (both at onset and at later stages of the disease) and not in that of multiorgan donors with type 2 diabetes or nondiabetic donors. These pancreas-infiltrating neutrophils mainly localized at the level of very small blood vessels. Our findings suggest the existence of a hitherto unrecognized clinical phenotype that might reflect unexplored pathogenic pathways underlying T1D.

Objectives: To validate the clinical significance of anti-IFI16 autoantibodies in SSc and assess their associations with serological markers of SSc. Methods: A semi-quantitative ELISA was used to detect anti-IFI16 autoantibodies in the sera of 344 SSc patients from seven Italian hospitals and 144 healthy controls. SSc-associated autoantibodies [anti-RNA polymerase III (anti-RNAP III) antibodies, anti-centromere, anti-topo I] and IF patterns were evaluated using commercial assays. Statistical analyses were performed to test clinical and serological associations. Results: The results of this study confirm a significant prevalence (29%) of anti-IFI16 antibodies in the SSc population (n = 344). Anti-IFI16 antibodies were also detected in 30% of the SSc patients who tested negative for both ACAs and anti-topo I (anti-Scl70) antibodies. In this subgroup of patients, anti-IFI16 antibodies were significantly associated with the limited cutaneous form of SSc with a sensitivity of 40% and a specificity of 81%. Moreover, analysis of the distribution of anti-RNAP III antibodies vs anti-IFI16 in the same SSc population showed that they were mutually exclusive. IIF revealed no association between anti-IFI16 and fluoroscopic patterns, due to a lack of IFI16 autoantigen in HEp-2 cells. Anti-IFI16 antibody levels were also significantly associated with heart involvement. Conclusions: Anti-IFI16 autoantibodies are frequently detected in SSc, displaying clinical and laboratory associations, and being particularly useful for diagnosis and disease classification in patients who are negative for other SSc serological markers. © The Author 2010. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.

The "Euro-Lupus Cohort" is composed by 1000 patients with systemic lupus erythematosus (SLE) that have been followed prospectively since 1991. These patients have been gathered by a European consortium-the "Euro-Lupus Project Group". This consortium was originated as part of the network promoted by the "European Working Party on SLE", a working group created in 1990 in order to promote research in Europe on the different problems related to this disease. The "Euro-Lupus Cohort" provides an updated information on the SLE morbidity and mortality characteristics in the present decade as well as defines several clinical and immunological prognostic factors. © 2005 Elsevier B.V. All rights reserved.

Arthritis Rheum. 2004 Dec;50(12):3934-40. Early response to immunosuppressive therapy predicts good renal outcome in lupus nephritis: lessons from long-term followup of patients in the Euro-Lupus Nephritis Trial. Houssiau FA, Vasconcelos C, D'Cruz D, Sebastiani GD, de Ramon Garrido E, Danieli MG, Abramovicz D, Blockmans D, Mathieu A, Direskeneli H, Galeazzi M, Gül A, Levy Y, Petera P, Popovic R, Petrovic R, Sinico RA, Cattaneo R, Font J, Depresseux G, Cosyns JP, Cervera R. Université Catholique de Louvain, Brussels, Belgium. houssiau@ruma.ucl.ac.be Abstract OBJECTIVE: In the Euro-Lupus Nephritis Trial (ELNT), 90 patients with lupus nephritis were randomly assigned to a high-dose intravenous cyclophosphamide (IV CYC) regimen (6 monthly pulses and 2 quarterly pulses with escalating doses) or a low-dose IV CYC regimen (6 pulses of 500 mg given at intervals of 2 weeks), each of which was followed by azathioprine (AZA). After a median followup of 41 months, a difference in efficacy between the 2 regimens was not observed. The present analysis was undertaken to extend the followup and to identify prognostic factors. METHODS: Renal function was prospectively assessed quarterly in all 90 patients except 5 who were lost to followup. Survival curves were derived using the Kaplan-Meier method. RESULTS: After a median followup of 73 months, there was no significant difference in the cumulative probability of end-stage renal disease or doubling of the serum creatinine level in patients who received the low-dose IV CYC regimen versus those who received the high-dose regimen. At long-term followup, 18 patients (8 receiving low-dose and 10 receiving high-dose treatment) had developed permanent renal impairment and were classified as having poor long-term renal outcome. We demonstrated by multivariate analysis that early response to therapy at 6 months (defined as a decrease in serum creatinine level and proteinuria

Objective: An Italian multicentre study was promoted in order to assess the accuracy of four anti-double-stranded DNA (dsDNA) antibody assays for SLE diagnosis and monitoring. Methods: Two hundred and twenty-three patients with established SLE according to ACR classification criteria were enrolled from 9 centres. They included 59 patients at first evaluation (disease duration

Most autoinflammatory disorders typically come out in the pediatric population, although a limited number of patients may experience disease onset during adulthood. To date, a late disease onset has been described only in familial Mediterranean fever, caused by mutations in the MEFV gene, and in tumor necrosis factor receptor-associated periodic syndrome, caused by mutations in the TNFRSF1A gene. The relative rarity and lack of information on adult-onset autoinflammatory diseases make it likely that mutations will be found in an even smaller percentage of cases. With the aim of improving the genetic diagnosis in adults with suspected autoinflammatory disorders, we recently identified a set of variables related to the probability of detecting gene mutations in MEFV and TNFRSF1A and, in addition, we have also proposed a diagnostic score for identifying those patients at high risk of carrying mutations in these genes. In the present study we evaluated the preliminary score sensitivity and specificity on a wider number of patients in order to validate the goodness of fit of the model. Two hundred and nineteen consecutive patients with a clinical history of periodic fever attacks were screened for mutations in MEFV and TNFRSF1A genes; detailed information about family/personal history and clinical manifestations were also collected. For the validation of the score we considered data both from the 110 patients used to build the preliminary diagnostic score and from the additional 219 patients enrolled in the present study, for a total number of 329 patients. Early age at disease onset, positive family history for recurrent fever episodes, thoracic pain, abdominal pain and skin rash, which are the variables that had previously been shown to be significantly associated with a positive genetic test result (12), were used for validation. On univariate analysis the associations with a positive genetic test were: age at onset (odds ratio [OR] 0.43, p=0.003), positive family history for recurrent fever episodes (OR 5.81, p