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Behçet’s syndrome (BS) is a rare systemic vasculitis characterized by different clinical manifestations. As no specific laboratory tests exist, the diagnosis relies on clinical criteria, and the differential diagnosis with other inflammatory diseases can be challenging. Indeed, in a relatively small proportion of patients, BS symptoms include only mucocutaneous, articular, gastrointestinal, and non-typical ocular manifestations, which are frequently found also in psoriatic arthritis (PsA). We investigate the ability of serum interleukin (IL)-36α—a pro-inflammatory cytokine involved in cutaneous and articular inflammatory diseases—to differentiate BS from PsA. A cross-sectional study was performed on 90 patients with BS, 80 with PsA and 80 healthy controls. Significantly lower IL-36α concentrations were found in patients with BS as compared to PsA, although in both groups IL-36α was significantly increased compared to healthy controls. An empirical cut-off of 420.6 pg/mL displayed a specificity of 0.93, with a sensitivity of 0.70 (AUC 0.82) in discriminating PsA from BS. This cut-off displayed a good diagnostic performance also in BS patients lacking highly specific BS manifestations. Our results indicate that IL-36α might be involved in the pathogenesis of both BS and PsA, and might be a candidate biomarker to support the differential diagnosis of BS.

The aim of this paper is to point out the design, development and deployment of the AutoInflammatory Disease Alliance (AIDA) International Registry for paediatric and adult patients with non-infectious uveitis (NIU).This is a physician-driven, population- and electronic-based registry implemented for both retrospective and prospective collection of real-world demographics, clinical, laboratory, instrumental and socioeconomic data of patients with uveitis and other non-infectious inflammatory ocular diseases recruited through the AIDA Network. Data recruitment, based on the Research Electronic Data Capture (REDCap) tool, is thought to collect standardised information for real-life research and has been developed to change over time according to future scientific acquisitions and potentially communicate with other similar instruments. Security, data quality and data governance are cornerstones of this platform.Ninety-five centres have been involved from 19 countries and four continents from 24 March to 16 November 2021. Forty-eight out of 95 have already obtained the approval from their local ethics committees. At present, the platform counts 259 users (95 principal investigators, 160 site investigators, 2 lead investigators, and 2 data managers). The AIDA Registry collects baseline and follow-up data using 3943 fields organised into 13 instruments, including patient's demographics, history, symptoms, trigger/risk factors, therapies and healthcare utilization for patients with NIU.The development of the AIDA Registry for patients with NIU will facilitate the collection of standardised data leading to real-world evidence and enabling international multicentre collaborative research through inclusion of patients and their families worldwide.

While precision medicine is still a challenge in rheumatic disease, in recent years many advances have been made regarding pathogenesis, the treatment of inflammatory arthropathies, and their interaction. New insight into the role of inflammasome and synovial tissue macrophage subsets as predictors of drug response give hope for future tailored therapeutic strategies and a personalized medicine approach in inflammatory arthropathies. Here, we discuss the main pathogenetic mechanisms and therapeutic approaches towards precision medicine in rheumatoid arthritis from the 2022 International GISEA/OEG Symposium.

ObjectiveInterleukin (IL)-1 inhibitors are largely employed in patients with Still’s disease; in cases with refractory arthritis, IL-6 inhibitors have shown to be effective on articular inflammatory involvement. The aim of the present study is to assess any difference in the effectiveness of the IL-1β antagonist canakinumab prescribed as first-line biologic agent between the systemic and the chronic-articular Still’s disease.MethodsData were drawn from the retrospective phase of the AutoInflammatory Disease Alliance (AIDA) international registry dedicated to Still’s disease. Patients with Still’s disease classified according to internationally accepted criteria (Yamaguchi criteria and/or Fautrel criteria) and treated with canakinumab as first-line biologic agent were enrolled.ResultsA total of 26 patients (17 females, 9 males; 18 patients developing Still’s disease after the age of 16 years) were enrolled; 16 (61.5%) patients suffered from the systemic pattern of the disease; 10 (38.5%) patients suffered from the chronic-articular type. No differences were observed between the systemic and the chronic-articular Still’s disease in the frequency of complete response, of flares after the start of canakinumab (p = 0.701) and in the persistence in therapy (p = 0.62). No statistical differences were observed between the two groups after 3 months, 12 months and at the last assessment in the decrease of: the systemic activity score (p = 0.06, p = 0.17, p = 0.17, respectively); the disease activity score on 28 joints (p = 0.54, p = 0.77, p = 0.98, respectively); the glucocorticoid dosage (p = 0.15, p = 0.50, and p = 0.50, respectively); the use of concomitant disease modifying anti-rheumatic drugs (p = 0.10, p = 1.00, and p = 1.00, respectively). No statistically significant differences were observed in the decrease of erythrocyte sedimentation rate (p = 0.34), C reactive protein (p = 0.48), and serum ferritin levels (p = 0.34) after the start of canakinumab.ConclusionCanakinumab used for Still’s disease has been effective in controlling both clinical and laboratory manifestations disregarding the type of disease course when used as first-line biotechnological agent. These excellent results might have been further enhanced by the early start of IL-1 inhibition.

© 2022 Elsevier Inc.Background/objectives: Long-term efficacy and safety of tocilizumab (TCZ) in adult-onset Still's disease (AOSD) mostly derive from small case series. Herein we report a registry-based study investigating TCZ efficacy and safety in a cohort of patients with AOSD evaluated by clinical and serum inflammatory markers as well as drug retention rate analysis. Methods: This is an international multicentre study analyzing data from patients with AOSD regularly enrolled in the AIDA registry. TCZ efficacy was evaluated between baseline and last follow-up assessment in terms of changes in the Pouchot score and laboratory findings. Drug-retention rate was estimated by the Kaplan-Meier method, while Cox-regression analysis was employed to detect potential predictive factors of treatment withdrawal. Results: Data from 31 patients (15 men, 16 women) refractory to the conventional therapies and treated with TCZ were extracted from the AIDA registry. Mean ± SD time of treatment duration with TCZ was 24.32 ± 20.57 months. Median (IRQ) Pouchot score significantly decreased throughout the study period (p=0.001) with a significant difference between baseline [2.00 (4.00)] and 6 month-follow-up [0.00 (0.00)] (p=0.003) and between baseline and last follow-up assessment [0.00 (0.00)] (p=0.032), while no differences were observed between 6 month-evaluation and last follow-up assessment (p=0.823). Similarly, laboratory parameters significantly decreased from baseline to the last follow-up visit. With regard to drug survival, cumulative TCZ retention rate at 12-, 24-, and 36-month follow-up visit were 83.1%, 71.7% and 63.7%, respectively, without significant differences between biologic naïve patients and those previously treated with other biologics (p=0.329). Likewise, no significant differences were observed between chronic articular course of AOSD and other types of disease course (p=0.938) or between patients co-administered with conventional immunosuppressants and patients receiving TCZ as monotherapy (p=0.778). Cox-regression analysis identified no variable associated with a higher hazard of treatment withdrawal. Treatment was discontinued in 9 patients due to long-term remission (n=4), adverse events (n=2), loss of efficacy (n=1), non-medical reason (n=1) and unspecified cause (n=1). Mean glucocorticosteroids daily dose significantly decreased from baseline (18.36 ± 24.72 mg) to the last follow-up assessment (4.02 ± 4.99 mg, p=0.003). Conclusions: TCZ allows control of disease activity as well as normalization of serum inflammatory markers in both systemic and chronic articular form of AOSD. Additionally, TCZ displays an excellent drug retention rate while minimizing the risk of long-term exposure to corticosteroids.

Conflicting results can be found in the literature on the frequency of hepatitis B virus (HBV) reactivation (HBVr) on rituximab (RTX) in rheumatic patients with previously resolved HBV (prHBV) infection. Here, we report the frequency of HBVr in a large historical cohort of caucasian rheumatic patients with prHBV receiving RTX. Registry data of rheumatic patients treated with RTX were retrospectively analysed. Demographic and clinical characteristics including evaluation of anti-HCV and HBV markers, annual HBV-DNA determination and aminotransferase levels assessed every three months, were recorded. Kaplan-Meier estimate was used to compare the risk of being still under therapy at different time points in patients with or without prHBV infection. Cox regression analysis was used to determine the association between recorded variables and treatment discontinuation. A total of 311 patients treated with RTX, 44 (14.1%) with and 267 (85.9%) without prHBV were analysed. No significant difference between the two groups regarding demographic and clinical characteristics was observed. During RTX treatment, detectable HBV-DNA and reappearance of HBsAg in patients with prHBV (seroreversion) were never observed. Kaplan-Meier functions were similar in patients with or without prHBV infection which was not associated with RTX discontinuation neither at univariate nor at multivariate analysis. These data are in favor of the concept that patients with rheumatologic diseases have a very low risk of reactivation of the HBV infection under RTX treatment. However, future prospective studies, including a larger number of patients, are still necessary to draw definitive conclusions.

The aim of the study is to evaluate the frequency and features of positive pathergy test (PPT) in Italy, its role in the diagnosis of Behçet's disease (BD), and any association with other BD-related manifestations. 52 BD patients, 52 patients with axial spondyloarthritis (ax-SpA), and 26 healthy controls (HCs) underwent intradermal injection of normal saline and intradermal needle soaked with fresh self-saliva. The results of pathergy tests were statistically analysed in the light of demographic, clinical, and therapeutic features of subjects enrolled. Pathergy test performed with saline resulted always negative in all groups. Skin prick test using self-saliva resulted in the occurrence of a papule in 3 (5.8%) BD patients and in 1 (1.9%) patient with ax-SpA. A ≥ 15mm erythematous area surrounding the needle prick site was observed in 22 (42.3%) BD patients, 5 (9.6%) patients with ax-SpA, and 2 (7.7%) HCs (p = 0.00002). The frequency of skin erythema was significantly more frequent in patients with BD than those with ax-SpA (p

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 p p 0.038) were identified as predictors of damage accrual, whereas the use of immunosuppressants showed a protective effect (OR 0.20, 95% CI 0.08–0.54, p Conclusion In BS, organ damage accrues over time, also in long-standing disease, resulting in an impairment of the perceived physical and mental health. Adequate immunosuppressive treatment, preventing disease flares and minimizing exposure to GCs have a crucial role in lowering the risk of damage accrual.

Behçet’s syndrome (BS) is a rare systemic vasculitis characterized by different clinical manifestations. As no specific laboratory tests exist, the diagnosis relies on clinical criteria, and the differential diagnosis with other inflammatory diseases can be challenging. Indeed, in a relatively small proportion of patients, BS symptoms include only mucocutaneous, articular, gastrointestinal, and non-typical ocular manifestations, which are frequently found also in psoriatic arthritis (PsA). We investigate the ability of serum interleukin (IL)-36α—a pro-inflammatory cytokine involved in cutaneous and articular inflammatory diseases—to differentiate BS from PsA. A cross-sectional study was performed on 90 patients with BS, 80 with PsA and 80 healthy controls. Significantly lower IL-36α concentrations were found in patients with BS as compared to PsA, although in both groups IL-36α was significantly increased compared to healthy controls. An empirical cut-off of 420.6 pg/mL displayed a specificity of 0.93, with a sensitivity of 0.70 (AUC 0.82) in discriminating PsA from BS. This cut-off displayed a good diagnostic performance also in BS patients lacking highly specific BS manifestations. Our results indicate that IL-36α might be involved in the pathogenesis of both BS and PsA, and might be a candidate biomarker to support the differential diagnosis of BS.

Rheumatoid arthritis (RA) patients on JAK inhibitors (JAKi) have an increased HZ risk compared to those on biologic DMARDs (bDMARDs). Recently, the Adjuvanted Recombinant Zoster Vaccine (RZV) became available worldwide, showing good effectiveness in patients with inflammatory arthritis. Nevertheless, direct evidence of the immunogenicity of such a vaccine in those on JAKi or anti-cellular bDMARDs is still lacking. This prospective study aimed to assess RZV immunogenicity and safety in RA patients receiving JAKi or anti-cellular bDMARDs that are known to lead to impaired immune response. Patients with classified RA according to ACR/EULAR 2010 criteria on different JAKi or anti-cellular biologics (namely, abatacept and rituximab) followed at the RA clinic of our tertiary center were prospectively observed. Patients received two shots of the RZV. Treatments were not discontinued. At the first and second shots, and one month after the second shot, from all patients with RA, a sample was collected and RZV immunogenicity was assessed and compared between the treatment groups and healthy controls (HCs) receiving RZV for routine vaccination. We also kept track of disease activity at different follow-up times. Fifty-two consecutive RA patients, 44 females (84.61%), with an average age (±SD) of 57.46 ± 11.64 years and mean disease duration of 80.80 ± 73.06 months, underwent complete RZV vaccination between February and June 2022 at our center. At the time of the second shot (1-month follow-up from baseline), anti-VZV IgG titer increased significantly in both groups with similar magnitude (bDMARDs: 2258.76 ± 897.07 mIU/mL; JAKi: 2059.19 ± 876.62 mIU/mL, p < 0.001 for both from baseline). At one-month follow-up from the second shot, anti-VZV IgG titers remained stable in the bDMARDs group (2347.46 ± 975.47) and increased significantly in the JAKi group (2582.65 ± 821.59 mIU/mL, p = 0.03); still, no difference was observed between groups comparing IgG levels at this follow-up time. No RA flare was recorded. No significant difference was shown among treatment groups and HCs. RZV immunogenicity is not impaired in RA patients on JAKi or anti-cellular bDMARDs. A single shot of RZV can lead to an anti-VZV immune response similar to HCs without discontinuing DMARDs.

Axial spondyloarthritis (axial-SpA) is a multifactorial disease characterized by inflammation in sacroiliac joints and spine, bone reabsorption, and aberrant bone deposition, which may lead to ankylosis. Disease pathogenesis depends on genetic, immunological, mechanical, and bioenvironmental factors. HLA-B27 represents the most important genetic factor, although the disease may also develop in its absence. This MHC class I molecule has been deeply studied from a molecular point of view. Different theories, including the arthritogenic peptide, the unfolded protein response, and HLA-B27 homodimers formation, have been proposed to explain its role. From an immunological point of view, a complex interplay between the innate and adaptive immune system is involved in disease onset. Unlike other systemic autoimmune diseases, the innate immune system in axial-SpA has a crucial role marked by abnormal activity of innate immune cells, including γδ T cells, type 3 innate lymphoid cells, neutrophils, and mucosal-associated invariant T cells, at tissue-specific sites prone to the disease. On the other hand, a T cell adaptive response would seem involved in axial-SpA pathogenesis as emphasized by several studies focusing on TCR low clonal heterogeneity and clonal expansions as well as an interindividual sharing of CD4/8 T cell receptors. As a result of this immune dysregulation, several proinflammatory molecules are produced following the activation of tangled intracellular pathways involved in pathomechanisms of axial-SpA. This review aims to expand the current understanding of axial-SpA pathogenesis, pointing out novel molecular mechanisms leading to disease development and to further investigate potential therapeutic targets.

Background Despite several studies having identified factors associated with successful treatment outcomes in rheumatoid arthritis (RA), there is a lack of accurate predictive models for sustained remission in patients on biologic agents. To the best of our knowledge, no machine learning (ML) approaches apart from logistic regression (LR) have ever been tried on this class of problems. Methods In this longitudinal study, patients with RA who started a biological disease-modifying antirheumatic drug (bDMARD) in a tertiary care center were analyzed. Demographic and clinical characteristics were collected at treatment baseline, 12-month, and 24-month follow-up. A wrapper feature selection algorithm was used to determine an attribute core set. Four different ML algorithms, namely, LR, random forest, K-nearest neighbors, and extreme gradient boosting, were then trained and validated with 10-fold cross-validation to predict 24-month sustained DAS28 (Disease Activity Score on 28 joints) remission. The performances of the algorithms were then compared assessing accuracy, precision, and recall. Results Our analysis included 367 patients (female 323/367, 88%) with mean age +/- SD of 53.7 +/- 12.5 years at bDMARD baseline. Sustained DAS28 remission was achieved by 175 (47.2%) of 367 patients. The attribute core set used to train algorithms included acute phase reactant levels, Clinical Disease Activity Index, Health Assessment Questionnaire-Disability Index, as well as several clinical characteristics. Extreme gradient boosting showed the best performance (accuracy, 72.7%; precision, 73.2%; recall, 68.1%), outperforming random forest (accuracy, 65.9%; precision, 65.6%; recall, 59.3%), LR (accuracy, 64.9%; precision, 62.6%; recall, 61.9%), and K-nearest neighbors (accuracy, 63%; precision, 61.5%; recall, 54.8%). Conclusions We showed that ML models can be used to predict sustained remission in RA patients on bDMARDs. Furthermore, our method only relies on a few easy-to-collect patient attributes. Our results are promising but need to be tested on longitudinal cohort studies.

Ultrasound-guided synovial tissue biopsy (USSB) may allow personalizing the treatment for patients with inflammatory arthritis. To this end, the quantification of tissue inflammation in synovial specimens can be crucial to adopt proper therapeutic strategies. This study aimed at investigating whether computer vision may be of aid in discriminating the grade of synovitis in patients undergoing USSB. We used a database of 150 photomicrographs of synovium from patients who underwent USSB. For each hematoxylin and eosin (H&E)-stained slide, Krenn’s score was calculated. After proper data pre-processing and fine-tuning, transfer learning on a ResNet34 convolutional neural network (CNN) was employed to discriminate between low and high-grade synovitis (Krenn’s score

ObjectiveThe present paper describes the design, development, and implementation of the AutoInflammatory Disease Alliance (AIDA) International Registry specifically dedicated to patients with Schnitzler's syndrome.MethodsThis is a clinical physician-driven, population- and electronic-based registry implemented for the retrospective and prospective collection of real-life data from patients with Schnitzler's syndrome; the registry is based on the Research Electronic Data Capture (REDCap) tool, which is designed to collect standardized information for clinical research, and has been realized to change over time according to future scientific acquisitions and potentially communicate with other existing or future similar registries.ResultsSince its launch, 113 centers from 23 countries in 4 continents have been involved. Fifty-seven have already obtained the approval from their local Ethics Committees. The platform counts 324 users (114 Principal Investigators, 205 Site Investigators, 2 Lead Investigators, and 3 data managers) at current (April 28th, 2022). The registry collects baseline and follow-up data using 3,924 fields organized into 25 instruments, including patient's demographics, history, clinical manifestations and symptoms, trigger/risk factors, laboratory, instrumental exams, therapies, socioeconomic information, and healthcare access.ConclusionsThis International Registry for patients with Schnitzler's syndrome facilitates standardized data collection, enabling international collaborative projects through data sharing and dissemination of knowledge; in turn, it will shed light into many blind spots characterizing this complex autoinflammatory disorder.

BackgroundPsoriatic Arthritis (PsA) is a multifactorial disease, and predicting remission is challenging. Machine learning (ML) is a promising tool for building multi-parametric models to predict clinical outcomes. We aimed at developing a ML algorithm to predict the probability of remission in PsA patients on treatment with Secukinumab (SEC).MethodsPsA patients undergoing SEC treatment between September 2017 and September 2020 were retrospectively analyzed. At baseline and 12-month follow-up, we retrieved demographic and clinical characteristics, including Body Mass Index (BMI), disease phenotypes, Disease Activity in PsA (DAPSA), Leeds Enthesitis Index (LEI) and presence/absence of comorbidities, including fibromyalgia and metabolic syndrome. Two random feature elimination wrappers, based on an eXtreme Gradient Boosting (XGBoost) and Logistic Regression (LR), were trained and validated with 10-fold cross-validation for predicting 12-month DAPSA remission with an attribute core set with the least number of predictors. The performance of each algorithm was assessed in terms of accuracy, precision, recall and area under receiver operating characteristic curve (AUROC).ResultsOne-hundred-nineteen patients were selected. At 12 months, 20 out of 119 patients (25.21%) achieved DAPSA remission. Accuracy and AUROC of XGBoost was of 0.97 ± 0.06 and 0.97 ± 0.07, overtaking LR (accuracy 0.73 ± 0.09, AUROC 0.78 ± 0.14). Baseline DAPSA, fibromyalgia and axial disease were the most important attributes for the algorithm and were negatively associated with 12-month DAPSA remission.ConclusionsA ML approach may identify SEC good responders. Patients with a high disease burden and axial disease with comorbid fibromyalgia seem challenging to treat.

BackgroundInferential statistical methods failed in identifying reliable biomarkers and risk factors for relapsing giant cell arteritis (GCA) after glucocorticoids (GCs) tapering. A ML approach allows to handle complex non-linear relationships between patient attributes that are hard to model with traditional statistical methods, merging them to output a forecast or a probability for a given outcome.ObjectiveThe objective of the study was to assess whether ML algorithms can predict GCA relapse after GCs tapering.MethodsGCA patients who underwent GCs therapy and regular follow-up visits for at least 12 months, were retrospectively analyzed and used for implementing 3 ML algorithms, namely, Logistic Regression (LR), Decision Tree (DT), and Random Forest (RF). The outcome of interest was disease relapse within 3 months during GCs tapering. After a ML variable selection method, based on a XGBoost wrapper, an attribute core set was used to train and test each algorithm using 5-fold cross-validation. The performance of each algorithm in both phases was assessed in terms of accuracy and area under receiver operating characteristic curve (AUROC).ResultsThe dataset consisted of 107 GCA patients (73 women, 68.2%) with mean age ( ± SD) 74.1 ( ± 8.5) years at presentation. GCA flare occurred in 40/107 patients (37.4%) within 3 months after GCs tapering. As a result of ML wrapper, the attribute core set with the least number of variables used for algorithm training included presence/absence of diabetes mellitus and concomitant polymyalgia rheumatica as well as erythrocyte sedimentation rate level at GCs baseline. RF showed the best performance, being significantly superior to other algorithms in accuracy (RF 71.4% vs LR 70.4% vs DT 62.9%). Consistently, RF precision (72.1%) was significantly greater than those of LR (62.6%) and DT (50.8%). Conversely, LR was superior to RF and DT in recall (RF 60% vs LR 62.5% vs DT 47.5%). Moreover, RF AUROC (0.76) was more significant compared to LR (0.73) and DT (0.65).ConclusionsRF algorithm can predict GCA relapse after GCs tapering with sufficient accuracy. To date, this is one of the most accurate predictive modelings for such outcome. This ML method represents a reproducible tool, capable of supporting clinicians in GCA patient management.

Summary The pathogenesis of psoriatic arthritis (PsA) involves several pathways, including the CD40/CD40L signaling which promotes the release of multiple cytokines. Transmembrane CD40L is also released in soluble form (sCD40L) and phosphodiesterase 4 (PDE4) seems to be involved in its cleavage. We aimed to investigate whether apremilast, a PDE4 inhibitor, could modify circulating levels of sCD40L in PsA patients, and the possible associations of these changes with clinical response. Consecutive PsA patients starting apremilast in routine clinical practice were prospectively observed. Disease Activity of Psoriatic Arthritis (DAPSA), Psoriasis Area Severity Index (PASI), Leeds Enthesitis Score (LEI) and serum samples were collected at baseline and at 6 months. Samples were run in a Bio-Plex ProTM plate for sCD40L. To investigate the association of sCD40L level with DAPSA based minor response, low disease activity (LDA) and/or remission at 6 months of treatment, multivariate logistic regression models with backward selection (P

To compare the efficacy of Adalimumab (ADA) in noninfectious anterior uveitis (AU) and posterior segment (PS) involvement, associated with different conditions, with a focus on Behcet’s syndrome (BS). In this retrospective, multicenter post-hoc study, we evaluated the efficacy of ADA in terms of ocular control and relapses in 96 patients with AU and PS uveitis, either idiopathic (IU) or associated with BS or with other systemic disorders (OSD) (Juvenile Idiopathic Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Vogt-Koyanagi-Harada, Inflammatory Bowel Disease), followed in three tertiary referral centers. Ninety-six patients (45 AU; 51 PS uveitis) were included. Eleven had IU, 58 BS, and 27 OSD. All patients with AU achieved complete long-term ocular control. In PS uveitis, 89%, 67% and 100% of patients with BS, IU and OSD achieved ocular control at the last follow-up (> 12 months), respectively. The lowest ocular relapse rate occurred in patients with AU with BS (1/13) or IU (0/2). ADA accounted for long-term disease control, and no predictors of ocular control and relapse were identified; particularly, ocular relapses seemed not related to systemic ones. Macular edema resolved in 75% and 67% of PS uveitis with BS and IU, respectively. ADA controls both anterior and posterior uveitis, with an efficacy similar in IU, BS and OSD patients. In BS, the efficacy of ADA seems to be independent of demographic and clinical characteristics, and ocular relapses mostly occurred independently from systemic ones. Based on our results, ADA may represent a valid alternative in anterior refractory uveitis.

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

Behcet’s syndrome (BS) is a multisystemic disorder displaying a marked variability across different geographic areas. The main aim of this study was to analyze demographic and clinical features of a cohort of BS patients diagnosed in three tertiary referral centers in Italy and detect potential associations between the different manifestations. Medical records of 396 patients (218 females, 178 males) were retrospectively analyzed. Mean age at onset was 30.00 ± 18.75 years with a female-to-male ratio of 1.22:1. Mucocutaneous features were the most frequent starting manifestations of BS, followed by eye inflammation. Erythema nodosum (p = 0.007), arthritis/arthralgias (p = 0.0115), and central nervous system (CNS) signs (p = 0.014) were significantly over-represented in female patients, whereas male gender was associated with lower mean age at onset (p = 0.031), higher frequency of pseudofollicular lesions, and uveitis (p = 0.00134 and p

Scanty data on the anti- SARS-CoV-2 IgG level decay after two-dose BNT162b2 vaccination have been published in patients with psoriatic arthritis (PsA) on TNF inhibitors (TNFi). Similarly, no reports on the immunogenicity of a booster dose in such patients have been provided yet.We aimed to investigate the IgG level decay after two-dose BNT162b2 vaccination and the immunogenicity and safety of the booster dose in PsA patients on TNFi.Forty patients with classified PsA on TNFi undergoing booster dose with the BNT162b2 mRNA SARS- CoV-2 vaccine (BioNTech/Pfizer) were enrolled. Fifteen days after the third shot, serum IgG levels against SARS-CoV-2 (Abbott®ARCHITECT i2000SR, positivity cut-off 50 AU/mL) were assayed in all patients. Clinimetrics and treatment data were gathered. TNFi treatment was not discontinued. Sera from healthcare professionals were considered as healthy controls for 1:1 propensity score-matching. Student's t-test and logistic regression were used for investigating differences in immunogenicity between groups and predictors of antibody response.Even though the decay of IgG levels showed similar magnitude between groups, PsA patients had a lower IgG level than matched controls at 4 months after two-dose vaccination (2009.22±4050.22 vs. 6206.59±4968.33 AU/mL, respectively p=0.0006). Booster dose restored IgG levels to a similar extent in both groups (15846.47±12876.48 vs. 20374.46±12797.08 AU/ml p=0.20, respectively). Clinical Disease Activity Index (CDAI) did not change before and after vaccination (6.68±4.38 vs. 4.95±4.20, p=0.19).A BNT162b2 booster dose should be recommended in PsA patients on TNFi as its administration restores anti-SARS-CoV-2 IgG levels similar to healthy individuals.

Few studies compared adalimumab to other targeted therapies in head-to-head randomized clinical trials (RCTs) for rheumatoid arthritis (RA), but multiple comparisons are not available. This Bayesian Network Meta-Analysis evaluated which targeted therapy is more likely to achieve ACR50 response with good safety at 24 weeks of treatment in RA. A systematic literature review was conducted for head-to-head phase 3 RCTs that compared adalimumab to other targeted therapies in combination with methotrexate (MTX) or as monotherapy to treat RA patients, and searched through MEDLINE, EMBASE, Cochrane Library and Clinicaltrial.gov. The outcomes of interest were ACR50 response and withdrawals due to adverse events at 24 weeks. WinBUGS 1.4 software (MRC Biostatistics Unit, Cambridge, UK) was used to perform the analyses, using a random effect model. Sixteen studies were included in the analysis. The most favorable SUCRA for the ACR50 response rate at 24 weeks of treatment in combination with MTX was ranked by upadacitinib, followed by baricitinib, tofacitinib and filgotinib. As monotherapy, the highest probability was ranked by tocilizumab followed by sarilumab. No significant differences in safety profile among treatment options were found. Jak-inhibitors in combination with MTX and interleukin-6 antagonism as monotherapy showed the highest probability to achieve ACR50 response after 24 weeks of treatment. None of assessed targeted therapies were associated to risk of withdrawal due to adverse events. Key messages: Direct and indirect comparison between adalimumab and other targeted therapies demonstrated some differences in terms of efficacy that may help to drive RA treatment. Jak-inhibitors and interleukine-6 antagonists ranked as first in the probability to achieve ACR50 response after 24 weeks of treatment in combination with methotrexate or monotherapy, respectively.

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.

ObjectiveAim of this paper is to illustrate the methodology, design, and development of the AutoInflammatory Disease Alliance (AIDA) International Registry dedicated to patients with the Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis (PFAPA) syndrome.MethodsThis is a physician-driven, non-population- and electronic-based registry proposed to gather real-world demographics, clinical, laboratory, instrumental and socioeconomic data from PFAPA patients. Data recruitment is realized through the on-line Research Electronic Data Capture (REDCap) tool. This registry is thought to collect standardized information for clinical research leading to solid real-life evidence. The international scope and the flexibility of the registry will facilitate the realization of cutting-edge study projects through the constant updating of variables and the possible merging and transfer of data between current and future PFAPA registries.ResultsA total of 112 centers have already been involved from 23 countries and 4 continents starting from August 24th, 2021, to April 6th, 2022. In total 56/112 have already obtained the formal approval from their local Ethics Committees. The platform counts 321 users (113 principal investigators, 203 site investigators, two lead investigators, and three data managers). The registry collects retrospective and prospective data using 3,856 fields organized into 25 instruments, including PFAPA patient's demographics, medical histories, symptoms, triggers/risk factors, therapies, and impact on the healthcare systems.ConclusionsThe development of the AIDA International Registry for PFAPA patients will enable the on-line collection of standardized data prompting real-life studies through the connection of worldwide groups of physicians and researchers. This project can be found on https://clinicaltrials.gov NCT 05200715.

ObjectiveAim of this paper is to present the design, construction, and modalities of dissemination of the AutoInflammatory Disease Alliance (AIDA) International Registry for patients with systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD), which are the pediatric and adult forms of the same autoinflammatory disorder.MethodsThis Registry is a clinical, physician-driven, population- and electronic-based instrument implemented for the retrospective and prospective collection of real-world data. The collection of data is based on the Research Electronic Data Capture (REDCap) tool and is intended to obtain evidence drawn from routine patients' management. The collection of standardized data is thought to bring knowledge about real-life clinical research and potentially communicate with other existing and future Registries dedicated to Still's disease. Moreover, it has been conceived to be flexible enough to easily change according to future scientific acquisitions.ResultsStarting from June 30th to February 7th, 2022, 110 Centers from 23 Countries in 4 continents have been involved. Fifty-four of these have already obtained the approval from their local Ethics Committees. Currently, the platform counts 290 users (111 Principal Investigators, 175 Site Investigators, 2 Lead Investigators, and 2 data managers). The Registry collects baseline and follow-up data using 4449 fields organized into 14 instruments, including patient's demographics, history, clinical manifestations and symptoms, trigger/risk factors, therapies and healthcare access.ConclusionsThis international Registry for patients with Still's disease will allow a robust clinical research through collection of standardized data, international consultation, dissemination of knowledge, and implementation of observational studies based on wide cohorts of patients followed-up for very long periods. Solid evidence drawn from “real-life” data represents the ultimate goal of this Registry, which has been implemented to significantly improve the overall management of patients with Still's disease. NCT 05200715 available at https://clinicaltrials.gov/.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination plays a crucial role as pivotal strategy to curb the coronavirus disease-19 (COVID-19) pandemic. The present study described the clinical status of patients affected by idiopathic inflammatory myopathies (IIM) after COVID-19 vaccination to assess the number of relapses. We included all patients affected by IIM and followed by Myositis Clinic, Rheumatology and Respiratory Diseases Units, Siena University Hospital, Bari University Hospital, Policlinico Umberto I, Sapienza University, Rome, and Policlinico Paolo Giaccone, Palermo. They underwent a telephone survey. A total of 119 IIM patients (median, IQR 58 (47–66) years; 32males; 50 dermatomyositis, 39 polymyositis and 30 anti-synthetase syndrome) were consecutively enrolled. Except four patients who refused the vaccination, 94 (81.7%) received Comirnaty, 16 (13.9%) Spikevax, 5 (4.4%) Vaxzevria. Seven (6.1%) patients had flare after vaccination. One of them had life-threatening systemic involvement and died two months after second dose of COVID-19 vaccination. From logistic regression analysis, Chi2-log ratio = 0.045,the variable that most influences the development of flare was the number of organs involved (p = 0.047). Sixty-eight patients received the third dose of COVID-19 vaccination: 51(75%) Comirnaty and 17 (25%) Moderna. No patients had flares after third dose. Our study represents the largest cohort of IIM patients in which the incidence of recurrence after anti-SARS-CoV-2 vaccine was assessed. In line with real-life data from other diseases, we found a clinical non-statistically significant risk of relapse in our patients, which occurred seldom, usually mild and in patients with a more severe and aggressive course of disease.

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.

Introduction This article points out the design, methods, development and deployment of the international registry promoted by the AutoInflammatory Disease Alliance (AIDA) Network with the aim to define and assess paediatric and adult patients with immune-mediated scleritis. Methods This registry collects both retrospective and prospective real-world data from patients with non-infectious scleritis through the Research Electronic Data Capture (REDCap) tool and aims to promote knowledge and real-life evidence from patients enrolled worldwide; the registry also allows the collection of standardised data, ensuring the highest levels of security and anonymity of patients' data and flexibility to change according to scientific acquisitions over time. The communication with other similar registries has been also ensured in order to pursue the sustainability of the project with respect to the adaptation of collected data to the most diverse research projects. Results Since the launch of the registry, 99 centres have been involved from 20 countries and four continents. Forty-eight of the centres have already obtained a formal approval from their local ethics committees. At present, the platform counts 259 users (95 principal investigators, 160 site investigators, 2 lead investigators, and 2 data managers); the platform collects baseline and follow-up data using 3683 fields organised into 13 instruments, including patient's demographics, history, symptoms, trigger or risk factors, therapies and healthcare utilization. Conclusions The development of the AIDA International Registry for patients with non-infectious scleritis will allow solid research on this rare condition. Real-world evidence resulting from standardised real-life data will lead to the optimisation of routine clinical and therapeutic management, which are currently limited by the rarity of this ocular inflammatory condition.

ObjectiveThis paper points out the design, development and deployment of the AutoInflammatory Disease Alliance (AIDA) International Registry dedicated to pediatric and adult patients affected by Undifferentiated Systemic AutoInflammatory Diseases (USAIDs).MethodsThis is an electronic registry employed for real-world data collection about demographics, clinical, laboratory, instrumental and socioeconomic data of USAIDs patients. Data recruitment, based on the Research Electronic Data Capture (REDCap) tool, is designed to obtain standardized information for real-life research. The instrument is endowed with flexibility, and it could change over time according to the scientific acquisitions and potentially communicate with other similar tools; this platform ensures security, data quality and data governance.ResultsThe focus of the AIDA project is connecting physicians and researchers from all over the world to shed a new light on heterogeneous rare diseases. Since its birth, 110 centers from 23 countries and 4 continents have joined the AIDA project. Fifty-four centers have already obtained the approval from their local Ethics Committees. Currently, the platform counts 290 users (111 Principal Investigators, 179 Site Investigators, 2 Lead Investigators, and 2 data managers). The Registry is collecting baseline and follow-up data using 3,769 fields organized into 23 instruments, which include demographics, history, symptoms, trigger/risk factors, therapies, and healthcare information access for USAIDs patients.ConclusionsThe development of the AIDA International Registry for USAIDs patients will facilitate the online collection of real standardized data, connecting a worldwide group of researchers: the Registry constitutes an international multicentre observational groundwork aimed at increasing the patient cohort of USAIDs in order to improve our knowledge of this peculiar cluster of autoinflammatory diseases. NCT 05200715 available at https://clinicaltrials.gov/.

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.

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

BackgroundScanty data on the immunogenicity of the BNT162b2 vaccine in patients with psoriatic arthritis (PsA) on Tumor Necrosis Factor inhibitors (TNFi) have been published.ObjectiveTo investigate the humoral response to BNT162b2 vaccination patients with PsA on TNFi, comparing immunogenicity with healthy controls.MethodsForty patients with classified PsA on TNFi undergoing vaccination with the BNT162b2 mRNA SARS-CoV-2 vaccine (BioNTech/Pfizer) were enrolled. Fifteen days after the second shot, serum IgG levels against SARS-CoV-2 (Abbott ARCHITECT i2000SR, positivity cut-off 50 AU/mL) were assayed in all patients. Clinimetrics and treatment data were gathered. TNFi treatment was not discontinued throughout the whole period, whereas methotrexate (MTX) was discontinued for 1 week after each shot in those on combination therapy. Sera from healthcare professionals were considered as healthy controls for 1:1 propensity score matching; any of them was taking medication.Student’s t-test and logistic regression were used for investigating differences in immunogenicity between groups and predictors of antibody response.ResultsClinical Disease Activity Index did not change before and after vaccination (7.06±5.23 to 7.10±5.27, p=0.92).Patients with PsA achieved a positive anti-SARS-CoV-2 IgG level with a mean (±SD) of 13794.44±15 815.42 AU/mL. Although lower, the antibody level was not significantly different from matched controls (19227.4±11.8460.45 AU/mL, p=0.08). In the overall sample, those on MTX (12/80, 15%) had a trend toward lower immune response (p=0.07); glucocorticoid therapy (11/80, 13.8%) predicted lower antibody levels (p=0.04).ConclusionsContinuing TNFi in patients with PsA throughout the vaccination did not hamper immunogenicity.

Schnitzler's syndrome is a rare autoinflammatory disease. Clinical response to IL-1 inhibitor drugs has been described, but limited information is available on the long-term efficacy and safety of these agents in Schnitzler's syndrome.A retrospective study was conducted of patients with Schnitzler's syndrome fulfilling Strasbourg diagnostic criteria followed in 9 Italian centres. The retention rate of IL-1 inhibitors was evaluated using Kaplan-Meier analysis.Fifteen of 20 patients with Schnitzler's syndrome were treated with IL-1 inhibitors: in total, they received 16 courses of anakinra (median duration 20.0 months [6.0-58.3]), and 8 courses of canakinumab (median duration 19.0 months [13.5-31.0]). The retention rate of IL-1 inhibitors was 73.4% [SE 9.4] at 1 year and 63.6% [SE 10.4] at 2 years. There was no significant difference between the retention rate of anakinra and canakinumab. The retention rate was higher in patients with a definite diagnosis according to the Strasbourg criteria as compared with those with a probable diagnosis (p=0.03). At the last follow-up visit, all patients who started therapy with IL-1 inhibitors were still on treatment, although in some cases with an increased dosage compared to the start of therapy. A sparing effect on the use of conventional synthetic disease-modifying anti-rheumatic drugs and a significant reduction of prednisone dosage (p=0.02) and of serum amyloid A (SAA) levels (p=0.03) were observed.The retention rate of IL-1 inhibitors in patients with Schnitzler's syndrome was high, particularly in patients with a definite diagnosis according to the Strasbourg criteria, reflecting their effectiveness in the treatment of this syndrome.

Objectives To evaluate the impact of FM on the clinical outcomes of biologics in patients with PsA in real life. Methods FM was diagnosed according to current criteria among PsA patients starting a first biologic drug from 2010 through 2017. At each visit, disease activity of PsA (DAPSA), minimal disease activity (MDA), HAQ, rate of patients achieving DAPSA-based low disease activity (LDA) or remission, and MDA were evaluated. Lost patients or those not achieving the target were imputed as non-responders. The drug survival was evaluated by Kaplan–Meyer analysis. Estimated hazard ratios (HRs) of discontinuing therapy or achieving MDA were assessed by multivariate regression models. Results A total of 238 patients, of whom 58 had also FM, started a first biologic drug. Compared with no-FM PsA, FM PsA patients were more frequently female (P = 0.0001) with polyarticular subset (P = 0.0001), and with higher mean BMI (P = 0.006). Drug survival was significantly lower in FM PsA (50%, mean 32 months) than in no-FM PsA (74%, mean 42 months, P = 0.0001). Rates of remission/LDA and MDA were significantly lower in FM PsA at 3, 6, 12 and 24 months (P < 0.001). Remission in FM PsA was negligible (3.4% and 0% at 3 and 6 months, respectively). Negative predictors of drug discontinuation were no FM (HR 0.51) and normal weight (HR 0.29), while no FM (HR 2.54) and male sex (HR 1.58) were positive predictors of long-standing MDA. Conclusions Comorbid FM, along with female gender and obesity seem to be the worst combination of negative prognostic factors in PsA.

Behçet's syndrome (BS) is a chronic (auto)-inflammatory disorder characterized by different clusters of symptoms, including mucocutaneous and ocular involvements. Interleukin-1 inhibitors anakinra (ANA), canakinumab (CAN), and gevokizumab (GEV) represent a promising therapeutic alternative in BS. To date, evidence on the use of ANA, CAN, and GEV is mainly based on small isolated studies or case series, and the real place of anti-IL1 agents in the treatment of BS is still unclear. We performed a systematic review of current evidence on the efficacy and safety of anti-IL1 agents in BS. The PubMed search yielded a total of 398 references, from which we retrieved 24 studies for inclusion (4 clinical trials, 6 observational studies, 14 case reports, case series or letters to the editor). Four studies evaluated the overall efficacy of IL-1 inhibitors, 15 studies focused on the specific efficacy of ANA, whereas efficacy of CAN and GEV was evaluated in 8 and 3 studies, respectively. Both ANA and CAN were associated with good control of mucocutaneous and ocular manifestations. ANA resulted effective also for osteoarticular manifestations. GEV was studied only for ocular manifestations, but gave contrasting results. Discordant evidence supports the use of ANA and CAN in pediatric setting and for first-line treatment of general BS manifestations. Most frequent side effects were local or diffuse cutaneous reactions and injection site reactions, particularly for ANA treatment. Blocking the IL-1 pathway could be an effective therapeutic strategy in particular BS involvements.

The current paradigm in the management of rheumatoid arthritis (RA) is to treat patients in the early stage of the disease (ERA). Previous meta-analysis-based mixed treatment comparisons (MTCs), aimed to identify the most effective drugs in ERA, are biased by the wide “window” of early definition, ranging from 6 months to 2 years. The aim of this study was to estimate through a Bayesian Network Meta-Analysis which biologics or small molecules are more likely to achieve a 1-year good clinical response in ERA patients with disease duration

The objective is to evaluate the effectiveness of a spacing strategy of bDMARDs in a cohort of selected patients in disease remission or low-disease activity (LDA) without glucocorticoids affected with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). This was a single-centre study carried out on patients prospectively enrolled in the biologic Apulian registry. Patients whose disease was in remission or LDA without taking glucocorticoids during the previous 6 months and who had agreed to increase the time interval between bDMARD doses were included in this study. Demographic and clinical characteristics were recorded at baseline and at 3, 6 and 12 months of follow-up. Endpoint of the study was the survival of spacing doses in the time lag of the study. Failure of spacing was defined as the first flare of disease. Thirty-seven RA, 28 PsA and 20 axSpA patients underwent bDMARD spacing according to a local strategy. During the follow-up, 5 RA, 6 PsA and 4 axSpA patients had a joint flare, but further 5 PsA patients manifested a skin relapse. Global persistence was 86.5% for RA (MST = 41 (95% CI: 37-45) months) and 80% for axSpA patients (MST = 36 (95% CI: 31-42) months). PsA patients showed a lower persistence, being of 60.7% (MST = 30 (95% CI: 23-36) months) (log-rank test, p = 0.03). Dose reduction by spacing bDMARD doses may be a feasible approach in patients with persistent remission/LDA activity. However, PsA patients might have greater odds of spacing failure because of skin psoriasis relapse. Key Points • Spacing of bDMARDs may be a feasible strategy for some patients with rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis who achieve the target and withdrawn glucocorticoids. • Psoriatic arthritis patients showed lower persistence because of both articular and skin relapses.

Behçet’s syndrome (BS) represents an understudied topic in pediatrics: the main aims of our study were to characterize demographic and clinical features of a cohort of BS patients with juvenile-onset managed in three tertiary referral centers in Italy, evaluate their evolution in the long-term, and detect any potential differences with BS patients having an adult-onset. Medical records of 64 juvenile-onset and 332 adult-onset BS followed-up over a 2-year period were retrospectively analyzed and compared. Mean age ± SD of first symptom-appearance was 10.92 ± 4.34 years with a female-to-male ratio of 1.06:1. Mucocutaneous signs were the most frequent initial manifestations, followed by uveitis. Throughout the disease course, genital aphthae (76.56%) and pseudofolliculitis (40.63%) prevailed among the mucocutaneous signs, while major organ involvement was represented by gastrointestinal and ocular involvement (43.75 and 34.38%, respectively). No significant differences emerged for both mucocutaneous signs and specific major organ involvement between juvenile-onset and adult BS patients. After excluding nonspecific abdominal pain, juvenile-onset BS patients were less frequently characterized by the development of major organ involvement (p = 0.027). Logistic regression detected the juvenile-onset as a variable associated with reduced risk of long-term major organ involvement (OR 0.495 [0.263–0.932],p = 0.029). In our cohort, juvenile-onset BS resembled the clinical spectrum of adult-onset patients. Pediatric patients with a full-blown disease at onset showed a more frequent mucocutaneous involvement. In addition, patients with juvenile-onset seemed to develop less frequently major organ involvement and had an overall less severe disease course.

EULAR recommendations do not suggest which biologic disease-modifying anti-rheumatic drug (bDMARD) should be preferred after failure of a first bDMARD in the treatment of rheumatoid arthritis (RA). In particular, few data are available regarding the effectiveness of a second-line bDMARD after failure of abatacept (ABA), tocilizumab (TCZ), and rituximab (RTX). The aim of this study was to analyze the retention rate of a second line with tumor necrosis factor inhibitors (TNFi) or other mechanisms of action (MoAs), after the failure of either RTX, TCZ, or ABA.Two hundred and seventy-eight RA patients from the Italian GISEA registry were included in the study. RTX was the first bDMARD in 18% of patients, ABA in 45.7%, and TCZ in 36.3%, while the second bDMARD was a TNFi (group 1) in 129 patients and an agent with a different MoA (group 2) in 149.During a median follow-up of 22 months (IQR 68), 129 patients discontinued their treatment; patients of group 1 discontinued the treatment more frequently than patients of group 2 (p0.001) with retention rates of 33.6±5.7% and 63.6±4.6% after 104 weeks for group 1 and group 2, respectively (p0.001). At multivariate analysis, the mechanism of action was the only predictor for the maintenance in therapy.According to our data, ABA, RTX, and TCZ seem to maintain a good retention rate also when used as a second-line therapy, suggesting their use after the failure of a non-TNFi as first-line therapy. However, specifically designed studies are needed to evaluate the more appropriate therapeutic strategies in RA, according to the first-line drug, including new targeted synthetic DMARDs. Key Points • A large proportion of rheumatoid arthritis patients fail the first biologic DMARD. • Few data are available about the efficacy of biologic DMARD after the failure of a non-TNF inhibitor. • Abatacept, rituximab, or tocilizumab seem to maintain a good retention rate after the failure of a first-course therapy with a non-TNF inhibitor.

Objective: To describe the role of biotechnological therapies in patients with tumor necrosis factor receptor associated periodic syndrome (TRAPS) and to identify any predictor of complete response.Methods: Clinical, laboratory, and therapeutic data from 44 Caucasian TRAPS patients treated with biologic agents were retrospectively collected in 16 Italian tertiary Centers.Results: A total of 55 biological courses with anakinra (n = 26), canakinumab (n = 16), anti-TNF-α agents (n = 10), and tocilizumab (n = 3) were analyzed. A complete response was observed in 41 (74.5%) cases, a partial response in 9 (16.4%) cases and a treatment failure in 5 (9.1%) cases. The frequency of TRAPS exacerbations was 458.2 flare/100 patients-year during the 12 months prior to the start of biologic treatment and 65.7 flare/100 patients-years during the first 12 months of therapy (p < 0.0001). The median duration of attacks was 5.00 (IQR = 10.50) days at the start of biologics and 1.00 (IQR = 0.00) days at the 12-month assessment (p < 0.0001). Likewise, a significant reduction was observed in the Autoinflammatory Disease Activity Index during the study period (p < 0.0001). A significant corticosteroid sparing effect was observed as early as the first 12 months of treatment both in the number of patients requiring corticosteroids (p = 0.025) and in the dosages employed (p < 0.0001). A significant reduction was identified in the erythrocyte sedimentation rate (p < 0.0001), C reactive protein (p < 0.0001), serum amyloid A (p < 0.0001), and in the 24-h proteinuria dosage during follow-up (p = 0.001). A relapsing-remitting disease course (OR = 0.027, C.I. 0.001–0.841, p = 0.040) and the frequency of relapses at the start of biologics (OR = 0.363, C.I. 0.301–0.953, p = 0.034) were significantly associated with a complete response. No serious adverse events were observed.Conclusions: Treatment with biologic agents is highly effective in controlling clinical and laboratory TRAPS manifestations. Patients with a relapsing-remitting course and a lower frequency of flares at the start of treatment show more likely a complete response to biologic agents.

Introduction: Only a few studies have reported the long-term efficacy of interleukin (IL)-1 inhibition in systemic juvenile idiopathic arthritis (sJIA) and adult onset Still’s disease (AOSD). We herein describe Anakinra (ANA) effectiveness expressed in terms of drug retention rate (DRR) and evaluate predictive factors of drug survival in sJIA and ASOD patients. Objectives: Examine the overall DRR of ANA in sJIA and AOSD patients. Explore the influence of biologic line of treatment, and the concomitant use of disease modifying anti-rheumatic drugs (cDMARDs) on DRR in the whole sample and stratified according to the disease thereafter; find eventual predictive factors associated with events leading to drug discontinuation. The corticosteroid (CS)- and cDMARDS-sparing effect, the impact of treatment delay on survival and the record of safety profile constituted ancillary aims. Methods: Medical records from 61 sJIA and 76 AOSD patients treated with ANA in 24 Italian tertiary referral centers were retrospectively reviewed. Results: The cumulative retention rate of ANA at 12-, 24-, 48- and 60-months of follow-up was 74.3%, 62.9%, 49.4% and 49.4% respectively, without any significant differences between sJIA and AOSD patients (p=0.164), and between patients treated in monotherapy compared to the subgroup co-administered with conventional cDMARDs (p=0.473). On the other hand, a significant difference in DRR was found between biologic-naive patients and those previously treated with biologic drugs (p=0.009), which persisted even after adjusting for pathology (p=0.013). In regression analysis, patients experiencing adverse events (AEs) (HR=3.029 [C.I. 1.750-5.242], p