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Abstract Objectives To explore the role of newly emerging autoantibodies (AAbs) - peptidyl-arginine deiminase 4 (aPAD4), carbamylated proteins (aCarP), and anti-RA33 (aRA33) - alongside the traditionally assessed rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA), in predicting the response to abatacept (ABT) and its retention rate in rheumatoid arthritis (RA) patients. Methods Data from 121 consecutive ABT-treated RA patients were recorded. The RF and ACPA status were retrospectively assessed by reviewing the patients’ clinical records. Positivity for aPAD4, aCarP and aRA33 were determined by Enzyme-Linked Immunosorbent Assay (ELISA). The achievement of a moderate or good EULAR response at 6 months and the 3-years retention were analyzed as treatment outcomes. Multiple logistic regression models and Cox regression hazard analysis models were built to identify the association between such outcomes and the different AAbs, after adjustment for different confounders. The AAbs were assessed both individually and in different combinations to identify the most robust predictive model. Results In the studied cohort, RF, ACPA, aPAD4, aCarP and aRA33-Ab tested positive in 74.4%, 69.4%, 43.8%, 23.9%, 14.9% patients, respectively. A moderate or good EULAR response at 6 months was achieved by 64.5% of subjects and the cumulative 3-years retention rate was 56.6%. A higher EULAR response rate was recorded in patient with positivity for RF (67% in subjects tested positive vs. 58% in negative), ACPA (68% vs. 57%), aPAD4 (68% vs. 62%), and aCarP (72% vs. 62%), although statistical significance was not reached likely due to sample size limitations. Similarly, ACPA, aPAD4, aCarP were associated with higher 3-year retention rates, though not statistically significant individually. The combined analysis revealed that positivity for ACPA and/or aPAD4 predicted a significantly higher EULAR response rate at 6 months compared with double negativity (adjusted OR 2.7, p 0.026). Furthermore, positivity for at least one of ACPA, aPAD4, or aCarP predicted a significantly higher 3-year ABT retention rate compared to triple negativity (62.1% single or double positive vs. 33.5% triple negative, adjusted HR 0.48, p 0.022). Conclusion This study highlights the potential benefits of using a combined assessment of ACPA aPAD4 and aCarP in predicting effectiveness of ABT in RA.

Abstract Introduction This study aims to characterize ocular manifestations of juvenile Behçet’s disease (jBD). Methods This was a registry-based observational prospective study. All subjects with jBD from the Autoinflammatory Diseases Alliance (AIDA) Network BD Registry showing ocular manifestations before 18 years were enrolled. Results We included 27 of 1000 subjects enrolled in the registry (66.7% male patients, 45 affected eyes). The median (interquartile range [IQR]) age at ocular involvement was 14.2 (4.7) years. Uveitis affected 91.1% of eyes (anterior 11.1%, posterior 40.0%, panuveitis 40.0%), retinal vasculitis 37.8% and other manifestations 19.8%. Later onset (p = 0.01) and male predominance (p = 0.04) characterized posterior involvement. Ocular complications occurred in 51.1% of eyes. Patients with complications had earlier onset (p

Objectives To explore the effects of anti-ribosomal P protein (anti-P) and anti-N-methyl-D-aspartic acid receptor subunit 2 (anti-NR2) autoantibodies on depression and cognitive dysfunction and their relationships with functional brain connectivity in SLE.Methods This cross-sectional study included adult patients who fulfilled the American College of Rheumatology/European Alliance of Associations for Rheumatology 2019 SLE criteria. Anti-P and anti-NR2 were quantified using ELISA. A 1-hour battery of neuropsychological testing interpreted by a neuropsychologist explored depressive symptoms (Center for Epidemiologic Studies Depression Scale, CES-D), cognitive domains and quality of life (SF-12). Resting-state functional connectivity (rs-fc) MRI analysis was performed within 1 month, and region-of-interest to region-of-interest (ROI-to-ROI) analyses with the graph theory were performed.Results Thirty-three patients with SLE (9% male) were enrolled, mean age (SD) of 43.5 (14) years and median disease duration of 10.4 years (2.9–25.4). Anti-P was positive in 6 (18.2%) and anti-NR2 in 14 (42.4%) patients. Depressive symptoms were found in 14 (42.4%) patients using the CES-D (range 0–51). After correction for age, disease duration, disease activity and white matter lesion load, the CES-D score was independently associated with anti-P serum level (β=0.32; p=0.049) and prednisone daily dose (β=0.38; p=0.023). Nineteen patients (57.6%) showed at least a cognitive test alteration, but no significant association with autoantibodies was found. The rs-fc MRI analysis revealed an independent association between the anti-P serum levels and many altered brain ROI properties but no anti-NR2 and prednisone effects on the cerebral network.Conclusions Anti-P was associated with brain network perturbation, which may be responsible for depressive symptoms in patients with SLE.

Background Fatigue is reported as the most prevalent symptom by patients with systemic lupus erythematosus (SLE). Fatigue management is complex due to its multifactorial nature. The aim of the study was to assess the usefulness of an innovative digital tool to manage fatigue in SLE, in a completely automated manner.Methods The «Lupus Expert System for Assessment of Fatigue» (LEAF) is free digital tool which measures the intensity and characteristics of fatigue and assesses disease activity, pain, insomnia, anxiety, depression, stress, fibromyalgia and physical activity using validated patient-reported instruments. Then, LEAF automatically provides personalised feedback and recommendations to cope with fatigue.Results Between May and November 2022, 1250 participants with SLE were included (95.2% women, median age 43yo (IQR: 34–51)). Significant fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue

Abstract Background This study aimed to investigate the trajectory of damage accrual, associated factors, and impact on health-related quality of life (HR-QoL) in a multicenter cohort of patients with Behçet’s syndrome (BS) over 2 years of follow-up. Methods Patients recruited in the BS Overall Damage Index (BODI) validation study were prospectively monitored for 2 years and assessed for damage accrual, defined as an increase ≥1 in the BODI score, and HR-QoL was evaluated by the SF-36 questionnaire. Logistic and multiple linear regression models were built to determine factors associated with damage accrual and impairment in the different SF-36 domains. Results During follow-up, 36 out of 189 (19.0%) patients had an increase ≥1 in the BODI score with a mean (SD) difference of 1.7 (0.8) (p

BackgroundIn psoriatic arthritis (PsA), the primary goal of treatment is clinical remission. This study aimed to characterize the molecular profile underlying the induced clinical remission in patients with PsA, comparing the remission state and the healthy condition.MethodsWhole blood transcriptomic analysis was performed on groups of 14 PsA patients in TNFi-induced clinical remission (DAPSA ≤ 4), 14 PsA patients with active disease (DAPSA > 14), and 14 healthy controls (HCs). Then, all differentially expressed genes (DEGs) derived from remission vs. HC comparison were analyzed for functional and biological characteristics by bioinformatics software. The gene expression of 12 genes was then validated by RT-qPCR in an extended cohort of 39 patients in clinical remission, 40 with active disease, and 40 HCs.ResultsThe transcriptomic analysis of PsA remission vs. HCs highlighted the presence of 125 DEGs, and out of these genes, 24 were coding genes and showed a great involvement in immune system processes and a functional network with significant interactions. The RT-qPCR validation confirming the down- and upregulation of FOS (FC −2.0; p 0.005) and CCDC50 (FC +1.5; p 0.005) genes, respectively, in line with their role in orchestrating inflammation and bone metabolism processes, may be related to PsA pathophysiology.ConclusionThe transcriptomic profile of clinical remission in PsA is similar to a healthy condition, but not identical, differing for the expression of FOS and CCDC50 genes, which appears to play a key role in its achievement.

IntroductionThe pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE) is widely unknown, and the role of autoantibodies is still undetermined.MethodsTo identify brain-reactive autoantibodies possibly related to NPSLE, immunofluorescence (IF) and transmission electron microscopy (TEM) on rat and human brains were performed. ELISA was used to reveal the presence of known circulating autoantibodies, while western blot (WB) was applied to characterize potential unknown autoantigen(s).ResultsWe enrolled 209 subjects, including patients affected by SLE (n=69), NPSLE (n=36), Multiple Sclerosis (MS, n=22), and 82 age- and gender-matched healthy donors (HD). Autoantibody reactivity by IF was observed in almost the entire rat brain (cortex, hippocampus, and cerebellum) using sera from NPSLE and SLE patients and was virtually negative in MS and HD. NPSLE showed higher prevalence (OR 2.4; p = 0.047), intensity, and titer of brain-reactive autoantibodies than SLE patients. Most of the patient sera with brain-reactive autoantibodies (75%) also stained human brains. Double staining experiments on rat brains mixing patients’ sera with antibodies directed against neuronal (NeuN) or glial markers showed autoantibody reactivity restricted to NeuN-containing neurons. Using TEM, the targets of brain-reactive autoantibodies were located in the nuclei and, to a lesser extent, in the cytoplasm and mitochondria. Given the high degree of colocalization between NeuN and brain-reactive autoantibodies, we assumed NeuN was a possible autoantigen. However, WB analysis with HEK293T cell lysates expressing or not expressing the gene encoding for NeuN protein (RIBFOX3) showed that patients’ sera carrying brain-reactive autoantibodies did not recognize the NeuN corresponding band size. Among the panel of NPSLE-associated autoantibodies (e.g., anti-NR2, anti-P-ribosomal protein, antiphospholipid) investigated by ELISA assay, only the anti-β2-glycoprotein-I (aβ2GPI) IgG was exclusively found in those sera containing brain-reactive autoantibodies.ConclusionIn conclusion, SLE and NPSLE patients possess brain-reactive autoantibodies but with higher frequency and titers found in NPSLE patients. Although many target antigens of brain-reactive autoantibodies are still undetermined, they likely include β2GPI.

IntroductionThis paper describes the creation and preliminary results of a patient-driven registry for the collection of patient-reported outcomes (PROs) and patient-reported experiences (PREs) in Behçet’s disease (BD).MethodsThe project was coordinated by the University of Siena and the Italian patient advocacy organization SIMBA (Associazione Italiana Sindrome e Malattia di Behçet), in the context of the AIDA (AutoInflammatory Diseases Alliance) Network programme. Quality of life, fatigue, socioeconomic impact of the disease and therapeutic adherence were selected as core domains to include in the registry.ResultsRespondents were reached via SIMBA communication channels in 167 cases (83.5%) and the AIDA Network affiliated clinical centers in 33 cases (16.5%). The median value of the Behçet’s Disease Quality of Life (BDQoL) score was 14 (IQR 11, range 0–30), indicating a medium quality of life, and the median Global Fatigue Index (GFI) was 38.7 (IQR 10.9, range 1–50), expressing a significant level of fatigue. The mean Beliefs about Medicines Questionnaire (BMQ) necessity-concern differential was 0.9 ± 1.1 (range – 1.8–4), showing that the registry participants prioritized necessity belief over concerns to a limited extent. As for the socioeconomic impact of BD, in 104 out of 187 cases (55.6%), patients had to pay from their own pocket for medical exams required to reach the diagnosis. The low family socioeconomic status (p

Objectives To analyse whether reported fatigue, one of the most challenging manifestations of systemic lupus erythematosus (SLE), may bias the assessment of disease activity in SLE according to the Physician Global Assessment (PGA).Methods Patients from the Lupus BioBank of the upper Rhein database, a cross-sectional multicentre collection of detailed clinical and biological data from patients with SLE, were included. Patients had to fulfil the 1997 American College of Rheumatology criteria for SLE and the PGA (0–3 scale) at the time of inclusion had to be available. Fatigue was assessed according to the Fatigue Scale for Motor and Cognitive Functions. Univariate and multivariate regression models were built to determine which variables were associated with the PGA.Results A total of 350 patients (89% female; median age: 42 years, IQR: 34–52) were included. The median Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score was 4 (IQR: 2–6). Of these 350 patients, 257 (73%) reported significant fatigue. The PGA (p=0.004) but not the SELENA-SLEDAI (p=0.43) was significantly associated with fatigue. Both fatigue and SELENA-SLEDAI were independently associated with the PGA in two different multivariate models.Conclusion Fatigue is independently associated with disease activity assessed using the PGA but not the SLEDAI. These findings highlight the fact that the PGA should capture only objectively active disease manifestations in order to improve its reliability.

Objective A subanalysis of the multicentre Early Lupus inception cohort was performed to investigate the real-world Glucocorticoids (GCs) Use in newly diagnosed systemic lupus erythematosus (SLE) Patients (GULP).Methods Patients starting prednisone (PDN) ≥5 mg/day and concomitant hydroxychloroquine or immunosuppressant within 12 months of SLE classification were enrolled. Core set variables were recorded at baseline and every 6 months, including changes in PDN dose, European Consensus Lupus Activity Measurement (ECLAM) and Systemic Lupus International Collaborating Clinics damage index. Regression models analysed predictors of tapering PDN

ObjectiveThe present manuscript aims to describe an international, electronic-based, user-friendly and interoperable patient registry for monogenic autoinflammatory diseases (mAIDs), developed in the contest of the Autoinflammatory Diseases Alliance (AIDA) Network.MethodsThis is an electronic platform, based on the Research Electronic Data Capture (REDCap) tool, used for real-world data collection of demographics, clinical, laboratory, instrumental and socioeconomic data of mAIDs patients. The instrument has flexibility, may change over time based on new scientific acquisitions, and communicate potentially with other similar registries; security, data quality and data governance are corner stones of the platform.ResultsAIDA project will share knowledge and expertise on mAIDs. Since its start, 118 centers from 24 countries and 4 continents have joined the AIDA project. Fifty-nine centers have already obtained the approval from their local Ethics Committees. Currently, the platform counts 337 users (122 Principal Investigators, 210 Site Investigators, 2 Lead Investigators, and 3 data managers). The Registry collects baseline and follow-up data using 3,748 fields organized into 21 instruments, which include demographics, patient history, symptoms, trigger/risk factors, therapies, and healthcare information for mAIDs patients.ConclusionsThe AIDA mAIDs Registry, acts both as a research tool for future collaborative real-life studies on mAIDs and as a service to connect all the figures called to participate. On this basis, the registry is expected to play a pivotal role in generating new scientific evidence on this group of rare diseases, substantially improving the management of patients, and optimizing the impact on the healthcare system. NCT 05200715 available at https://clinicaltrials.gov.

ObjectiveThe aim of this paper is to present the AutoInflammatory Disease Alliance (AIDA) international Registry dedicated to Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome, describing its design, construction, and modalities of dissemination.MethodsThis Registry is a clinical, physician-driven, population- and electronic-based instrument designed for the retrospective and prospective collection of real-life data. Data gathering is based on the Research Electronic Data Capture (REDCap) tool and is intended to obtain real-world evidence for daily patients' management. The Registry may potentially communicate with other on-line tools dedicated to VEXAS syndrome, thus enhancing international collaboration and data sharing for research purposes. The Registry is practical enough to be easily modified to meet future needs regarding VEXAS syndrome.ResultsTo date (April 22nd, 2022), 113 Centers from 23 Countries in 4 continents have been involved; 324 users (114 Principal Investigators, 205 Site Investigators, 2 Lead Investigators, and 3 data managers) are currently able to access the registry for data entry (or data sharing) and collection. The Registry includes 4,952 fields organized into 18 instruments designed to fully describe patient's details about demographics, clinical manifestations, symptoms, histologic details about skin and bone marrow biopsies and aspirate, laboratory features, complications, comorbidities, therapies, and healthcare access.ConclusionThis international Registry for patients with VEXAS syndrome will allow the achievement of a comprehensive knowledge about this new disease, with the final goal to obtain real-world evidence for daily clinical practice, especially in relation to the comprehension of this disease about the natural history and the possible therapeutic approaches. This Project can be found on https://clinicaltrials.gov NCT05200715.

Behçet's syndrome (BS) represents a challenging condition, characterized by a variable spectrum of disease profile and associated with a significant limitation of the daily activities as well as a potential negative impact on relationships and psychological status. Considering also the complexity of the therapeutic management of BS, that often includes biological off-label treatments, the participation in the therapeutic decision-making process of the BS patients is essential to ensure the integration of the care process into the life of the patient. For this reason, the empowerment of BS patients represents a crucial need and the present work is aimed at fully exploring all the potential variables implicated in the BS patient empowerment, also highlighting major points to consider and concrete actions to be planned in the immediate future in order to implement a pragmatic facilitation of the patients' empowerment.

Background: This study aims at describing the therapeutic outcome of patients carrying the R92Q variant in the TNFRSF1A gene treated with anakinra (ANA) or canakinumab (CAN) and identifying any factors predictive of complete response to IL-1 inhibition. Methods: Clinical data of patients treated with ANA or CAN for recurrent inflammatory attacks due to the presence of the R92Q variant were retrospectively collected and analysed. Results: Data about 20 treatment courses with IL-1 inhibitors (16 with ANA and 4 with CAN) from 19 patients were collected. Mean age at disease onset was 20.2 ± 14.8 years. In 5 cases (26%) the R92Q variant was found in a family member affected by recurrent fever. The therapeutic response was complete in 13(68%) and partial in 2 patients (11%); treatment failure was observed in 4 cases (21%). Median AIDAI decreased from 10 (interquartile range [IQR] = 28) to 0 (IQR = 1) at the 12-month follow-up visit ( p

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.

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 from post-hoc analyses based on PsA patients with concomitant peripheral and axial manifestations. Furthermore, the current trials and post-hoc analysis 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.

Objective To develop and validate the evidence-based and consensus-based Behçet’s Syndrome Overall Damage Index (BODI).Methods Starting 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.Results The 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, p

Background: Aim of this study was to search for any difference in the outcome of patients with adult onset Still's disease (AOSD) treated with anakinra (ANK) in relation with the interval between disease onset and the start of anti-interleukin(IL)-1 treatment and according with the different lines of ANK treatment.Patients and Methods: One hundred and forty-one AOSD patients treated with ANK have been retrospectively assessed. Statistically significant differences (p < 0.05) were analyzed in the frequency of ANK effectiveness, primary or secondary inefficacy to ANK and rate of resolution of clinical and laboratory AOSD manifestations after 3, 6, and 12 months since ANK treatment according with different lines of treatment and different times between AOSD onset and start of ANK.Results: No significant differences were identified in the ANK effectiveness and frequency of primary or secondary inefficacy for patients starting ANK within 6 months (p = 0.19, p = 0.14, and p = 0.81, respectively) or 12 months (p = 0.37, p = 0.23, and p = 0.81, respectively) since AOSD onset compared with patients starting ANK thereafter; no significant differences were identified in ANK effectiveness and primary or secondary inefficacy according with different lines of ANK treatment (p = 0.06, p = 0.19, and p = 0.13, respectively). Patients starting ANK within 6 and 12 months since AOSD onset showed a significantly quicker decrease of erythrocyte sedimentation rate and C-reactive protein than observed among patients undergoing ANK treatment after 6 and 12 months. The number of swollen joints at the 3 month follow-up visit was significantly lower among patients undergoing ANK within 6 months since AOSD onset (p = 0.01), while no significance was identified at the 6 and 12 month assessments (p = 0.23 and p = 0.45, respectively). At the 3 and 6 month visits, the number of swollen joints was significantly higher among patients previously treated with conventional and biological disease modifying anti-rheumatic drugs (DMARDs) compared with those formerly treated only with conventional DMARDs (p < 0.017).Conclusions: Clinical and therapeutic outcomes are substantially independent of how early ANK treatment is started in AOSD patients. However, a faster ANK effectiveness in controlling systemic inflammation and resolving articular manifestations may be observed in patients benefiting from IL-1 inhibition as soon as after disease onset.

About 20% of patients with a history of atherosclerotic cardiovascular disease will experience further cardiovascular events despite maximal pharmacological treatment with cardioprotective drugs. This highlights the presence of residual cardiovascular risk in a significant proportion of patients and the need for novel, more effective therapies. These therapies should ideally target different pathophysiological pathways involved in the onset and the progression of atherosclerosis, particularly the inflammatory and immune pathways. Methotrexate is a firstline disease-modifying antirheumatic drug that is widely used for the management of autoimmune and chronic inflammatory disorders. There is some in vitro and in vivo evidence that methotrexate might exert a unique combination of antiinflammatory, blood pressure lowering, and vasculoprotective effects. Pending the results of large prospective studies investigating surrogate end-points as well as morbidity and mortality, repurposing methotrexate for cardiovascular risk management might represent a cost-effective strategy with immediate public health benefits. This review discusses the current challenges in the management of cardiovascular disease; the available evidence on the effects of methotrexate on inflammation, blood pressure, and surrogate markers of arterial function; suggestions for future research directions; and practical considerations with the use of methotrexate in this context.

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.

Abstract Background The aim was to assess the attainability and outcome of the lupus low disease activity state (LLDAS) in the early stages of systemic lupus erythematosus (SLE). Methods LLDAS prevalence was evaluated at 6 (T1) and 18 (T2) months after diagnosis and treatment initiation (T0) in a monocentric cohort of 107 (median disease duration 9.7 months) prospectively followed Caucasian patients with SLE. Reasons for failure to achieve LLDAS were also investigated. Multivariate models were built to identify factors associated with lack of LLDAS achievement and to investigate the relationship between LLDAS and Systemic Lupus International Collaboration Clinics (SLICC)/Damage Index (SDI) accrual. Results There were 47 (43.9%) patients in LLDAS at T1 and 48 (44.9%) at T2. The most frequent unmet LLDAS criterion was prednisolone dose >7.5 mg/day (83% of patients with no LLDAS at T1). Disease manifestations with the lowest remission rate during follow up were increased anti-double-stranded DNA (persistently present in 85.7% and 67.5% of cases at T1 and T2, respectively), low serum complement fractions (73.2% and 66.3%) and renal abnormalities (46.4% and 28.6%). Renal involvement at T0 was significantly associated with failure to achieve LLDAS both at T1 (OR 7.8, 95% CI 1.4–43.4; p = 0.019) and T2 (OR 3.9, 95% CI 1.4–10.6; p = 0.008). Presence of any organ damage (SDI ≥1) at T2 was significantly associated with lack of LLDAS at T1 (OR 5.0, 95% CI 1.5–16.6; p = 0.009) and older age at diagnosis (OR 1.05 per year, 95% CI 1.01–1.09; p = 0.020). Conclusion LLDAS is a promising treatment target in the early stages of SLE, being attainable and negatively associated with damage accrual, but it fit poorly to patients with renal involvement.

This study explores demographic, clinical, and therapeutic features of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) in a cohort of 80 patients recruited from 19 Italian referral Centers. Patients’ data were collected retrospectively and then analyzed according to age groups (disease onset before or after 16 years) and genotype (high penetrance (HP) and low penetrance (LP) TNFRSF1A gene variants). Pediatric- and adult-onset were reported, respectively, in 44 and 36 patients; HP and LP variants were found, respectively, in 32 and 44 cases. A positive family history for recurrent fever was reported more frequently in the pediatric group than in the adult group (p

Background: Anakinra (ANA) is an effective treatment choice in patients with adult onset Still’s disease (AOSD). Variables affecting treatment survival include loss of efficacy or adverse events, but also the decision to discontinue treatment after long-term clinical remission.Objectives: Aims of this study were: (i) to assess the drug retention rate (DRR) of ANA during a long-term follow-up looking for any difference related to the line of biologic treatment, the concomitant use of conventional disease modifying anti-rheumatic drugs (cDMARDs) and the different type of AOSD (systemic versus chronic articular); (ii) to identify predictive factors of lack of efficacy, loss of efficacy, and ANA withdrawal owing to long-term remission.Methods: AOSD patients classified according with Yamaguchi criteria and treated with ANA were retrospectively enrolled in 18 Italian tertiary Centers. Demographic, laboratory, clinical and therapeutic data related to the start of ANA (baseline), the 3-month assessment and the last follow-up visit while on ANA treatment were retrospectively collected and statistically analyzed.Results: One hundred and forty-one AOSD patients (48 males, 93 females) treated with ANA for a mean period of 35.96 ± 36.05 months were enrolled. The overall DRR of ANA was 44.6 and 30.5% at the 60- and 120-month assessments, respectively, with no significant differences between: (i) biologic naïve patients and those previously treated with other biologics (log-rank p = 0.97); (ii) monotherapy and concomitant use of cDMARDs (log-rank p = 0.45); (iii) systemic and chronic articular types of AOSD (log-rank p = 0.67). No variables collected at baseline could predict primary inefficacy, while the number of swollen joints at baseline was significantly associated with secondary inefficacy (p = 0.01, OR = 1.194, C.I. 1.043–1.367). The typical AOSD skin rash was negatively related with ANA withdrawal owing to long-term remission (p = 0.03, OR = 0.224, C.I. 0.058–0.863).Conclusion: Long-term DRR of ANA has been found excellent and is not affected by different lines of biologic treatment, concomitant use of cDMARDs, or type of AOSD. The risk of losing ANA efficacy increases along with the number of swollen joints at the start of therapy, while the typical skin rash is a negative predictor of ANA withdrawal related to sustained remission.

Objective: Neonatal Lupus (NL) is a rare syndrome caused by placental transfer of maternal anti-SSA/Ro and anti-La/SSB autoantibodies to the fetus. The rarity of this condition requires the establishment of multidisciplinary registries in order to improve our knowledge.Method: Inclusion criteria in this retrospective study were the maternal confirmed positivity for anti-SSA/Ro and/or anti-SSB/La antibodies, and the presence of II or III degree congenital heart block (CHB) in utero or neonatal period (up to 27 days after birth).Result: Eighty-nine cases of CHB were observed in 85 women with 88 pregnancies that occurred between 1969 and 2017. CHB was mostly detected in utero (84 cases, 94.2%), while five cases were observed in the neonatal period. A permanent pacemaker was implanted in 51 of 73 children born alive (69.8), whereas global mortality rate was 25.8% (23 cases): 16 in utero, five perinatal, and two during childhood. By univariate analysis, factors associated with fetal death were pleural effusion (p = 0.005, OR > 100; CI 95% 2.88->100 and hydrops (p = 0.003, OR = 14.09; CI 95% 2.01–122). Fluorinated steroids (FS) were administered in 71.4% pregnancies, and its use was not associated with better survival. Some centers treated all cases with fluorinated steroids and some centers did not treat any case. CHB was initially incomplete in 24 fetuses, and of them five cases of II degree block reverted to a lower degree block after treatments. Recurrence rate in subsequent pregnancies was 17.6% (3 out of 17). A prophylactic treatment was introduced in 10 of these 16 subsequent (58.8%) pregnancies, mostly with FS or high dose intravenous immunoglobulins.Conclusion: This is the first report from the Italian Registry of neonatal lupus/CHB. The live birth rate was nearly 80%, with nearly two thirds of the children requiring the implantation of a pacemaker. The management of fetuses diagnosed with CHB was heterogeneous across Italian Centers. The registry at present is mainly rheumatological, but involvement of pediatric cardiologists and gynecologists is planned.

Abstract HLA-B*27 is strongly associated with an inflammatory autoimmune disorder, the Ankylosing Spondylitis (AS) and plays a protective role in viral infections. The two aspects might be linked. In this work, we compared in B*2705/B*07 positive patients with AS, the CD8+ T cell responses to two immunodominant EBV-derived epitopes restricted for either the HLA-B*27 (pEBNA3C) or the HLA-B*07 (pEBNA3A). We have unexpectedly found that the HLA-B*07-restricted EBNA3A peptide is presented by both the B*0702 and the B*2705 but not by the non AS-associated B*2709, that differs from the AS-associated B*2705 for a single amino acid in the peptide-binding groove (His116Asp). We then analyzed 38 B*2705-positive/B*07-negative (31 AS-patients and 7 healthy donors) and 8 B*2709-positive/B*07-negative subjects. EBNA3A-specific CD8+ T lymphocytes were present in 55.3% of the HLA-B*2705 but in none of the B*2709 donors (p = 0.0049). TCR β-chain analysis identified common TCRBV and TCRBJ gene segments and shared CDR3β sequences in pEBNA3A-responsive CTLs of B*2705 carriers, suggesting the existence of a shared TCR repertoire for recognition of the uncanonical B*2705/pEBNA3A complex. These data highlight the plasticity of the AS-associated HLA-B*2705, which presents peptides with suboptimal binding motifs, possibly contributing both to its enhanced capacity to protect against pathogens and to predispose to autoimmunity.

BACKGROUND:Behçet's disease (BD) is a polygenic immune-mediated disorder characterized by a close association with the HLA-B*51 allele. The HLA region has a strong linkage disequilibrium (LD) and carries several genetic variants (e.g. MIC-A, TNF-α genes) identified as associated to BD because of their LD with HLA-B*51. In fact, the HLA-B*51 is inherited as part of extended HLA haplotypes which are well preserved in patients with BD. Sardinian population is highly differentiated from other Mediterranean populations because of a distinctive genetic structure with very highly preserved HLA haplotypes. PATIENTS AND METHODS:In order to identify other genes of susceptibility to BD within the HLA region we investigated the distribution of human Allograft Inflammatory Factor-1 (AIF-1) gene variants among BD patients and healthy controls from Sardinia. Six (rs2736182; rs2259571; rs2269475; rs2857597; rs13195276; rs4711274) AIF-1 single nucleotide polymorphisms (SNPs) and related extended haplotypes have been investigated as well as their LD within the HLA region and with HLA-B*51. Overall, 64 BD patients, 43 HLA-B*51 positive healthy controls (HC) and 70 random HC were enrolled in the study. RESULTS:HLA-B*51 was the only allele with significantly higher frequency (pc = 0.0021) in BD patients (40.6%) than in HC (9.8%). The rs2259571T AIF-1 variant had a significantly reduced phenotypic, but not allelic frequency in BD patients (72.1%; pc = 0.014) compared to healthy population (91.3%). That was likely due to the LD between HLA-B*51 and rs2259571G (pc = 9E-5), even though the rs2259571G distribution did not significantly differ between BD patients and HC. CONCLUSION:No significant difference in distribution of AIF-1 SNPs haplotypes was observed between BD patients and HC and between HLA-B*51 positive BD patients and HLA-B*51 positive HC. Taken together, these results suggest that AIF-1 gene is not associated with susceptibility to BD in Sardinia.

Cardiovascular (CV) morbidity and mortality are a challenge in management of patients with systemic lupus erythematosus (SLE). Higher risk of CV disease in SLE patients is mostly related to accelerated atherosclerosis. Nevertheless, high prevalence of traditional cardiovascular risk factors in SLE patients does not fully explain the increased CV risk. Despite the pathological bases of accelerated atherosclerosis are not fully understood, it is thought that this process is driven by the complex interplay between SLE and atherosclerosis pathogenesis. Hydroxychloroquine (HCQ) is a cornerstone in treatment of SLE patients and has been thought to exert a broad spectrum of beneficial effects on disease activity, prevention of damage accrual, and mortality. Furthermore, HCQ is thought to protect against accelerated atherosclerosis targeting toll-like receptor signaling, cytokine production, T-cell and monocyte activation, oxidative stress, and endothelial dysfunction. HCQ was also described to have beneficial effects on traditional CV risk factors, such as dyslipidemia and diabetes. In conclusion, despite lacking randomized controlled trials unambiguously proving the protection of HCQ against accelerated atherosclerosis and incidence of CV events in SLE patients, evidence analyzed in this review is in favor of its beneficial effect.

Objectives. To define the prevalence and determinants of peripheral microvascular endothelial dysfunction (ED) in a large series of rheumatoid arthritis (RA) patients free of previous cardiovascular events. Materials and Methods. Data from 874 RA patients enrolled in the EDRA study (Endothelial Dysfunction Evaluation for Coronary Heart Disease Risk Estimation in Rheumatoid Arthritis—ClinicalTrials.gov: NCT02341066) were analyzed. Log-transformed reactive hyperemia index (Ln-RHI) was evaluated by peripheral arterial tonometry (PAT) using the EndoPAT2000 device: values of Ln-RHI

Background: Interleukin (IL)-1 plays a crucial role in the pathogenesis of Adult onset Still’s disease (AOSD).Objectives: To evaluate the efficacy and safety of anakinra (ANA) and canakinumab (CAN) in a large group of AOSD patients.Methods: Data on clinical, serological features, and concomitant treatments were retrospectively collected at baseline and after 3, 6, and 12 months from AOSD patients (Yamaguchi criteria) referred by 18 Italian centers. Pouchot’s score was used to evaluate disease severity.Results: One hundred forty patients were treated with ANA; 4 were subsequently switched to CAN after ANA failure. The systemic pattern of AOSD was identified in 104 (74.2%) of the ANA-treated and in 3 (75%) of the CAN-treated groups; the chronic-articular type of AOSD was identified in 48 (25.8%) of the ANA-treated and in 1 (25%) of the CAN-treated groups. Methotrexate (MTX) was the most frequent disease modifying anti-rheumatic drug (DMARD) used before beginning ANA or CAN [91/140 (75.8%), 2/4 (50%), respectively]. As a second-line biologic DMARD therapy in 29/140 (20.7%) of the patients, ANA was found effective in improving all clinical and serological manifestations (p < 0.0001), and Pouchot’s score was found to be significantly reduced at all time points (p < 0.0001). No differences in treatment response were identified in the ANA-group when the patients were stratified according to age, sex, disease pattern or mono/combination therapy profile. ANA primary and secondary inefficacy at the 12-month time point was 15/140 (10.7%) and 11/140 (7.8%), respectively. Adverse events (AEs) [mainly represented by in situ (28/47, 59.5%) or diffuse (12/47, 25.5%) skin reactions and infections (7/47, 14.8%)] were the main causes for discontinuation. Pouchot’s score and clinical and serological features were significantly ameliorated at all time points (p < 0.0001) in the CAN-group, and no AEs were registered during CAN therapy. Treatment was suspended for loss of efficacy only in one case (1/4, 25%).Conclusion: This is the largest retrospective observational study evaluating the efficacy and safety of IL-1 inhibitors in AOSD patients. A good response was noted at 3 months after therapy onset in both the ANA- and CAN-groups. Skin reaction may nevertheless represent a non-negligible AE during ANA treatment.

Current clinical practice suggests that recovering the hand functionality lost or reduced by injuries, interventions, and chronic diseases requires, beyond pharmacological treatments, a kinesiotherapic intervention. This form of rehabilitation consists of physical exercises adapted to the specific pathology. Its effectiveness is strongly dependent on the patient's adhesion to such a program. In this paper, we present a novel device with remote monitoring capabilities expressly conceived for the needs of rheumatic patients. It comprises several sensorized tools and can be used either in an outpatient clinic for hand functional evaluation, connected to a PC, or afforded to the patient for home kinesiotherapic sessions. In the latter case, the device guides the patient in the rehabilitation session, transmitting the relevant statistics about his performance to a TCP/IP server exploiting a GSM/GPRS connection for deferred analysis. An approved clinical trial has been set up in Italy, involving 10 patients with rheumatoid arthritis and 10 with systemic sclerosis, enrolled for 12 weeks in a home rehabilitation program with the proposed device. Their evaluation has been performed not only with traditional methods, but also with the proposed device. Subjective (hand algofunctional Dreiser's index) and objective (ROM, strength, and dexterity) parameters showed a sustained improvement throughout the follow-up. The obtained results proved that the device is an effective and safe tool for assessing hand disability and monitoring kinesiotherapy exercise, portending the potential exploitability of such a methodology in the clinical practice.

There is good epidemiological evidence that patients with autoimmune rheumatic disease states, particularly rheumatoid arthritis, have an increased risk of cardiovascular morbidity and mortality when compared to the general population. The presence of a chronic systemic proinflammatory state in this patient group disrupts the structural and functional integrity of the endothelium and the arterial wall, favouring the onset and progression of atherosclerosis. A significant role in the detrimental effects of inflammation on endothelial function and vascular homeostasis is played by specific proatherosclerotic cytokines such as tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6). Recent systematic reviews and meta-analyses have shown that treatment with methotrexate, a first-line disease-modifying antirheumatic drug (DMARD), is associated with a significant reduction in atherosclerosis-mediated cardiovascular events, such as myocardial infarction and stroke, and mortality, when compared to other DMARDs. This suggests that methotrexate might exert specific protective effects against vascular inflammation and atherosclerosis in the context of autoimmune rheumatic disease. This review discusses the available evidence regarding the potential antiatherosclerotic effects of methotrexate through the inhibition of TNF-α, IL-1, and IL-6 and provides suggestions for future experimental and human studies addressing this issue.