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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

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

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.

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) 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

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: The advent of biologic agents has revolutionized therapeutic approaches in systemic juvenile idiopatic arthritis (sJIA) as their introduction has been shown to modify disease course and improve overall outcomes, particularly when initiated early. Few studies have reported the drug retention rate (DRR) of biologic drugs in JIA, and none of them has specifically investigated the DRR of interleukin (IL)-1 inhibitors on sJIA. Objectives: The primary aim of the study was to examine the overall DRR of IL-1 blockers in sJIA patients. Secondary aims of our study were to: (i) explore the influence of biologic line of treatment, adverse events (AEs), type of anti-IL-1 agent and the concomitant use of conventional disease modifying anti-rheumatic drugs (cDMARDs) on DRR; (ii) find eventual predictive factors associated with events leading to drug discontinuation. The corticosteroid sparing effect and the impact of disease duration and treatment delay on survival constituted ancillary aims. Methods: sJIA patients – diagnosed according to the revised International League of Association for Rheumatology (ILAR) criteria – treated with anakinra (ANA) and canakinumab (CAN) were enrolled in 15 Italian tertiary referral centers. Demographic, clinical and therapeutic data collected from medical records were retrospectively collected and statistically analyzed. Results: Seventy seven patients were enrolled for a total of 86 treatment courses. The cumulative retention rate of the IL-1 inhibitors at 12-, 24-, 48-, and 60-months of follow-up was 79.9, 59.5, 53.5, and 53.5%, respectively, without any statistically significant differences between ANA and CAN (p = 0.056), and between patients treated in monotherapy compared to the subgroup co-administered with conventional immunosuppressors (p = 0.058). On the contrary, significant differences were found between biologic-naive patients and those previously treated with biologic drugs (p = 0.038) and when distinguishing according to AEs occurrence (p = 0.04). In regression analysis, patients pre-treated with other biologics (HR = 3.357 [CI: 1.341–8.406], p = 0.01) and those experiencing AEs (HR = 2.970 [CI: 1.186–7.435], p = 0.020) were associated with a higher hazard ratio of IL-1 inhibitors withdrawal. The mean treatment delay was significantly higher among patients discontinuing IL-1 inhibitors (p = 0.0002). Conclusion: Our findings suggest an excellent overall DRR for both ANA and CAN that might be further augmented by paying attention to AEs and employing these agents as first-line biologics in an early disease phase.

AIM Little is known about possible predictors of long-term survival on biologic disease-modifying antirheumatic drugs (bDMARD) after achievement of deep clinical remission in rheumatoid arthritis (RA) patients. We aimed at assessing factors associated with drug persistence of the first bDMARD in RA patients who achieved Simplified Disease Activity Index (SDAI) remission. METHODS The clinical charts of RA patients beginning a first bDMARD were retrospectively reviewed, and those who achieved SDAI-based remission were selected for this analysis. Drug retention rate and mean survival time (MST) were estimated using Kaplan-Meier curves, and hazard ratios (HRs) of discontinuing bDMARD were estimated by multivariate Cox-regression models. RESULTS Eight-six patients were on SDAI remission, and the survival rate of bDMARDs since 'baseline-time' was 82.6% (MST = 77.8 (95% CI: 69-86) months). Once on remission, patients not taking concomitant glucocorticoids had significantly higher survival rate (90.7%, MST = 86.3 (95% CI: 78-95) months) than patients who continued to intake low dose of glucocorticoids (68.8%, MST = 56.9 (95% CI: 45-69) months; P = .008). On the contrary, those patients assuming methotrexate (MTX) had significantly higher survival (87.7% (MST = 81.8 (95% CI: 73-91) months) than patients who were not taking MTX (66.7% (MST = 55.3 (95% CI: 40-71) months) (log-rank 4.72, P = .03). After the achievement of disease remission, stopping glucocorticoids (HR 0.31, 95% CI: 0.10-0.93) and methotrexate co-therapy (HR 0.34, 95% CI: 0.12-0.98) were independently associated with a lower risk of bDMARD discontinuation. CONCLUSIONS Among RA patients on clinical remission with a first bDMARD, those stopping glucocorticoids and continuing MTX had much longer survival on bDMARD.

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<0.05). With reference to clinical features during attacks, pericarditis and myalgia were reported more frequently in the context of adult-onset disease than in the pediatric age (with p<0.01 and p<0.05, respectively), while abdominal pain was present in 84% of children and in 25% of adults (p<0.01). Abdominal pain was significantly associated also to the presence of HP mutations (p<0.01), while oral aphthosis was more frequently found in the LP variant group (p<0.05). Systemic amyloidosis occurred in 25% of subjects carrying HP variants. As concerns laboratory features, HP mutations were significantly associated to higher ESR values (p<0.01) and to the persistence of steadily elevated inflammatory markers during asymptomatic periods (p<0.05). The presence of mutations involving a cysteine residue, abdominal pain, and lymphadenopathy during flares significantly correlated with the risk of developing amyloidosis and renal impairment. Conversely, the administration of colchicine negatively correlated to the development of pathologic proteinuria (p<0.05). Both NSAIDs and colchicine were used as monotherapy more frequently in the LP group compared to the HP group (p<0.01). Biologic agents were prescribed to 49 (61%) patients; R92Q subjects were more frequently on NSAIDs monotherapy than other patients (p<0.01); nevertheless, they required biologic therapy in 53.1% of cases. At disease onset, the latest classification criteria for TRAPS were fulfilled by 64/80 (80%) patients (clinical plus genetic items) and 46/80 (57.5%) patients (clinical items only). No statistically significant differences were found in the sensitivity of the classification criteria according to age at onset and according to genotype (p<0.05). This study describes one of the widest cohorts of TRAPS patients in the literature, suggesting that the clinical expression of this syndrome is more influenced by the penetrance of the mutation rather than by the age at onset itself. Given the high phenotypic heterogeneity of the disease, a definite diagnosis should rely on both accurate working clinical assessment and complementary genotype.

Objectives. The primary aim of our study was to evaluate long-term efficacy of secukinumab (SCK) in patients with axial spondyloarthritis (axSpA); secondary aims were to evaluate drug retention rate and to identify differences in the clinical and laboratory assessment according to axSpA clinical features, dosage administered, and biologic treatment lines.Patients and Methods. We collected clinical, demographical, and treatment data from 39 patients affected by axSpA consecutively treated with SCK. Laboratory assessment was based on inflammation parameters; clinical assessment was performed with the Ankylosing Spondylitis Disease Activity Score- (ASDAS-) CRP and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Data were recorded at baseline and every 3 months for the first year and then every 6 months in the second year.Results. Twelve males and 27 females were enrolled; both BASDAI and ASDAS-CRP showed a statistically significant reduction during the observation period (p<0.0001andp<0.0001, respectively). C-reactive protein significantly decreased (p=0.006), with significant reduction at the post hoc analysis between baseline and both 6-month evaluation (p=0.02) and 24-month visit (p=0.036). No statistical significance was observed in BASDAI and ASDAS-CRP improvement (p=0.482andp=0.164, respectively) between different dosages administered. No significant differences emerged in the BASDAI and ASDAS-CRP variations between biologic-naïve patients and subjects previously failing to tumour necrosis factor (TNF) inhibitors (p=0.53andp=0.148, respectively). At the end of our observation, 7 out of 39 patients discontinued SCK. The global retention rate at the end of the study period was 78.2%, without any significant differences between biologic-naïve and anti-TNF-failure patients (p=0.619) or between subjects administered with different SCK dosages (p=0.614). No adverse events were reported.Conclusions. In our cohort, SCK has proved a remarkable effectiveness regardless biologic treatment line and dosages employed. As suggested by the notable drug retention rate, SCK has been able to maintain its effectiveness over a considerable long period of treatment.

ObjectiveTo evaluate the effectiveness and safety of secukinumab in patients with a mucosal and articular Behçet’s phenotype resistant to conventional and biologic treatment.MethodsA multicentre retrospective study was performed on 15 patients with a mucosal and articular phenotype of Behçet’s syndrome fulfilling the International Criteria for Behçet’s Disease and refractory to treatment with colchicine, disease-modifying antirheumatic drugs and at least one antitumour necrosis factor-α agent. Minimum follow-up was set at 6 months. Six patients with a polyarticular involvement were treated with secukinumab 300 mg/month, while all other cases received secukinumab 150 mg/month. Dose increase from 150 to 300 mg per month and shortening of administration frequency were allowed for poor disease control. Response evaluation was based on the number of oral ulcers in the previous 28 days and Disease Activity Score-28 for articular manifestations.ResultsAt 3 months of follow-up, nine (66.7%) patients achieved a response (complete or partial), and this proportion further increased to 86.7% at 6 months, 76.9% at 12 months, 90.0% at 18 months and 100.0% after 24 months. Notably, all patients who started with secukinumab 300 mg/month achieved complete response by month 6. Seven (46.7%) patients could achieve a response only after switching to a higher dosage.ConclusionsOur study suggests that secukinumab at a dose of 150 and 300 mg per month is safe and effective for the long-term treatment of patients with Behçet’s syndrome with a mucosal and articular phenotype refractory to previous treatments. Notably, secukinumab 300 mg/month resulted in superior complete mucosal and articular responses with no serious or dose-related adverse effects.

Background. Interleukin-1 inhibition has revealed to be a successful treatment approach for patients with adult-onset Still’s disease (AOSD). However, real-life experience is focused on the use of anakinra, while data about canakinumab (CAN) are mainly based on case reports and small case series. Patients and Methods. Patients classified with AOSD according to Yamaguchi criteria and treated with CAN were consecutively enrolled. Their clinical and therapeutic data were retrospectively collected and statistically analysed to assess the role of CAN as a therapeutic opportunity in AOSD patients in terms of clinical and laboratory disease control along with corticosteroid-sparing effect. Results. Nine AOSD patients (8 females and 1 male) treated with CAN for 15.00 ± 12.3 months were enrolled. Resolution of clinical manifestations was reported in 8/9 cases at the 3-month assessment; a significant decrease in the number of tender joints ( p = 0.009 ), swollen joints ( p = 0.027 ), and disease activity score on 28 joints-C-reactive protein (DAS28-CRP) ( p = 0.044 ) was observed during the study period. The systemic score of disease activity significantly decreased at the 3-month and 6-month assessments and at the last visit compared to the start of treatment ( p = 0.028 , p = 0.028 , and p = 0.018 , respectively). The daily corticosteroid dosage was significantly reduced at the 3-month and at the last follow-up visits ( p = 0.017 and p = 0.018 , respectively). None of the patients experienced adverse events or severe adverse events during the follow-up. Conclusions. CAN has shown prompt and remarkable effectiveness in controlling AOSD activity in a real-life contest, with a significant glucocorticoid-sparing effect and an excellent safety profile.

Treatment of Behçet's syndrome (BS) is aimed at controlling all symptoms of such a complex disorder, ensuring a good quality of life and preventing life-threatening complications. A better understanding of the pathogenic role of different chemokines has improved our knowledge of BS and elicited a more specific use of therapies currently available, minimizing the burden of potential side-effects related to treatment.This work aims to provide a detailed overview of the safety profile for current therapies available in the treatment of BS, focusing on the main side-effects, toxicity and contraindications.The greatest experience in the management of BS has been achieved with the employment of monoclonal anti-tumor necrosis factor antibodies which have been advocated for BS refractory manifestations. Moreover, interleukin-1 inhibitors have proven to be effective as well as safe, despite escalation of their dosage, especially to manage the most severe and difficult-to-treat ocular manifestations. However, general treatment of BS patients remains awkward as protean clinical features may respond differently to the same treatment or even worsen. Therefore, patients' safety for therapies used in BS promotes the implementation of precision medicine, which could help targeting accurately the pathogenetic mechanisms concealed behind specific clinical phenotypes.

Recurrent pericarditis (RP) is a troublesome and debilitating complication of acute pericarditis. Although the etiopathogenesis of this condition remains unknown, an intricate overlap of autoimmune and autoinflammatory pathways has been hypothesized to explain its beginning and recurrence over time. The majority of cases are defined as "idiopathic", reflecting our awkwardness to unravel the intimate mechanisms of RP. Given the possible occurrence of anti-nuclear, anti-heart and anti-intercalated disk antibodies as well as the association with peculiar human leukocyte antigen haplotypes, an autoimmune contribution has been claimed to specify the nature of RP. However, the most innovative pathogenic scenario of RP has been conferred to the innate immune system, mainly involving neutrophils and macrophages that produce a large amount of interleukin (IL)-1 via inflammasome activation. The clinical resemblance of RP with autoinflammatory diseases that may be marked by symptomatic serositis, high fevers and strikingly increased inflammatory parameters further suggests a similar inflammasome-mediated pathogenesis. Aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) remain the mainstay of therapy in RP, whereas colchicine is recommended on top of standard anti-inflammatory therapy, due to its role in inhibiting the IL-1 converting enzyme (caspase 1) within the inflammasome as well as the release of additional pro-inflammatory mediators and reactive oxygen species. With regard to treatment of RP refractory to NSAIDs and colchicine, blockade of IL-1 is the most relevant advance achieved in the last decade: the outstanding effect of the short-acting IL-1 receptor antagonist anakinra has been first recognized in the pediatric population, giving a proof of its practical feasibility. Over a more recent time, a growing experience with anakinra deriving from both large and small studies has further confirmed that RP might be regarded as an IL-1-mediated disease. This review aims to provide a contemporary insight into the mechanisms leading to RP as well as into the most recent literature data showing the beneficial approach originating from IL-1 blockade in this intriguing disorder.

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.

Objective. To assess the efficacy of biologic drugs, beyond tumor necrosis factor- (TNF-) α inhibitors, in the management of noninfectious refractory scleritis, either idiopathic or associated with systemic immune-mediated disorders. Patients and Methods. This is a retrospective study assessing the efficacy of several biologic agents (rituximab, anakinra, tocilizumab, and abatacept) and the small molecule tofacitinib in the treatment of scleritis through assessment of scleral inflammation and relapses, as well as treatment impact on best-corrected visual acuity (BCVA) and safety profile. Results. Fourteen patients (19 eyes) were enrolled in the study. Scleritis inflammatory grading significantly improved from baseline to 3 months (p=0.002) and from baseline to the last follow-up visit (p=0.002). Scleritis relapses significantly decreased between the 12 months preceding and following biologic therapy (p=0.007). No differences regarding BCVA were observed (p=0.67). Regarding adverse events, only one patient developed pneumonia and septic shock under rituximab treatment. Conclusions. Our results, though limited to a low number of patients, highlight the effectiveness of different biologic therapies in the treatment of noninfectious refractory scleritis, showing to control scleral inflammation and allowing a significant reduction in the number of relapses.

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

Aims Novel therapies are needed for recurrent pericarditis, particularly when corticosteroid dependent and colchicine resistant. Based on limited data, interleukin-1 blockade with anakinra may be beneficial. The aim of this multicentre registry was to evaluate the broader effectiveness and safety of anakinra in a ‘real world’ population. Methods and results This registry enrolled consecutive patients with recurrent pericarditis who were corticosteroid dependent and colchicine resistant and treated with anakinra. The primary outcome was the pericarditis recurrence rate after treatment. Secondary outcomes included emergency department visits, hospitalisations, corticosteroid use and adverse events. Among 224 patients (46 ± 14 years old, 63% women, 75% idiopathic), the median duration of disease was 17 months (interquartile range 9–33). Most patients had elevated C-reactive protein (91%) and pericardial effusion (88%). After a median treatment of 6 months (3–12), pericarditis recurrences were reduced six-fold (2.33–0.39 per patient per year), emergency department admissions were reduced 11-fold (1.08–0.10 per patient per year), hospitalisations were reduced seven-fold (0.99–0.13 per patient per year). Corticosteroid use was decreased by anakinra (respectively from 80% to 27%; P Conclusion In patients with recurrent pericarditis, anakinra appears efficacious and safe in reducing recurrences, emergency department admissions and hospitalisations.

Background: Recent expiry of patents for tumor necrosis factor (TNF)-α inhibitors has led to the employment of biosimilars in clinical practice. The aim of the study was to identify any change in the control of ocular inflammatory manifestations among patients with non-infectious uveitis switching from an originator to a corresponding anti-TNF-α biosimilar. Methods: Thirty-seven consecutive patients (62 eyes involved) with non-infectious uveitis undergoing the switch from anti-TNF-α originators to biosimilars were retrospectively enrolled; the frequency of ocular flares before and after the switch as well as best corrected visual acuity (BCVA), central macular thickness (CMT), daily systemic corticosteroid intake, and frequency of uveitic macular edema (UME) at the switch and at the following assessments were statistically analysed. Results: The number of ocular flares during the 12 months preceding the switch was 16, corresponding to 3.6 flares/100 patients/12 months; the number of flares after the switch was 14, corresponding to 2.0 flares/100 patients/12 months. No statistically significant differences were identified in the frequency of flares (p = 0.84) and in the number of patients experiencing ocular flares (p = 0.39) between the twelve months preceding the switch and the period thereafter. No statistically significant changes were observed in the BCVA (p = 0.27), CMT (p = 0.50), frequency of UME (p = 0.57) and daily corticosteroid intake (p = 0.42) between the time of the switch and the last follow-up visit. Conclusions: The switch to biosimilars represents a feasible treatment choice associated with the maintenance of clinical efficacy in patients with non-infectious uveitis previously treated with the corresponding originator anti-TNF-α biologic agents.

The aim of the present study was to compare long-term adalimumab (ADA) and infliximab (IFX) retention rates in patients with intermediate, posterior, or panuveitis. Additional aims are as follows: (i) to identify any difference in the causes of treatment discontinuation between patients treated with ADA and IFX; (ii) to assess any impact of demographic features, concomitant treatments, and different lines of biologic therapy on ADA and IFX retention rates; and (iii) to identify any correlation between ADA and IFX treatment duration and the age at uveitis onset, the age at onset of the associated systemic diseases, and the age at the start of treatment. Clinical, therapeutic, and demographic data from patients with non-infectious intermediate, posterior, or panuveitis treated with ADA or IFX were retrospectively collected. Kaplan-Meier plot and log-rank (Mantel-Cox) test were used to assess survival curves. One hundred eight patients (188 eyes) were enrolled; in 87 (80.6%) patients, uveitis was associated with a systemic disease. ADA and IFX were administered in 62 and 46 patients, respectively. No statistically significant differences were identified between ADA and IFX retention rates (p value = 0.22). Similarly, no differences were identified between ADA and IFX retention rates in relation to gender (p value = 0.61 for males, p value = 0.09 for females), monotherapy (p value = 0.08), combination therapy with conventional disease-modifying antirheumatic drugs (log-rank p value = 0.63), and different lines of biologic therapy (p value = 0.79 for biologic-naïve patients; p value = 0.81 for subjects previously treated with other biologics). In conclusion, ADA and IFX have similar long-term retention rates in patients with non-infectious intermediate, posterior, and panuveitis. Demographic, clinical, and therapeutic features do not affect their long-term effectiveness.

Background:Evidence on the efficacy of Mepolizumab (MEPO) in Eosinophilic Granulomatosis with Polyangiitis (EGPA) is scarce [1].Objectives:To assess the efficacy and safety of MEPO in real-life clinical practice.Methods:We retrospectively included patients diagnosed with EGPA and treated with MEPO (100 or 300 mg/month). MEPO efficacy was evaluated in the first 12 months in terms of systemic disease and asthma control. The occurrence of any adverse event (AE) was recorded.Results:142 patients were included (38% males; median age 46.4 (IQR 36.7-54.4); 110 and 32 on MEPO 100 and 300 mg/month, respectively). General, ear-nose-throat, pulmonary, and neurological symptoms significantly decreased during treatment (table 1). MEPO accounted for a significant reduction in the BVAS (figure 1) and for a steroid sparing effect (figure 2). The proportion of patients with asthma attacks decreased by 90% at 12 months compared to t0, and asthma-related emergency accesses dropped from 17.4% to 2.3%. Overall, 21.1% of patients had a non-serious AE.Table 1.Control of clinical symptomsMEPO beginning (t0)3 monthsp-value(t3 vs t0)6 monthsp-value(t6 vs t0)12 monthsp-value(t12 vs t0)N obsN=142N=135N=123N=89General symptoms40 (28.2%)17 (12.6%)19 (15.5%)13 (14.6%)0.002Cutaneous manifestations13 (9.2%)6 (4.4%)0.0085 (4.1%)0.0254 (4.5%)0.180ENT manifestations106 (74.7%)52 (38.5%)44 (35.8%)29 (32.6%)Pulmonary manifestations130 (91.6%)59 (43.7%)39 (31.7%)28 (31.5%)Cardiac manifestations6 (4.2%)2 (1.5%)0.0832 (1.6%)0.08300.157Intestinal manifestations10 (7.0%)1 (0.7%)0.0054 (3.3%)0.0593 (3.4%)0.059Renal manifestations5 (3.5%)3 (2.2%)0.41400.0461 (1.1%)0.317Neurological manifestations36 (25.4%)22 (16.3%)0.01218 (14.6%)0.00310 (11.2%)0.035Figure 1.Changes in BVASFigure 2.Steroid treatmentConclusion:MEPO effectively controlled systemic and respiratory EGPA symptoms in a large European cohort, with no major safety concerns.References:[1]Wechsler et al. MEPO or Placebo for Eosinophilic Granulomatosis with Polyangiitis. NEJM. 2017Disclosure of Interests:Alessandra Bettiol: None declared, Maria Letizia Urban: None declared, Federico Alberici: None declared, Carlo Agostini: None declared, Chiara Baldini: None declared, Enrica Bozzolo: None declared, Paolo Cameli: None declared, Nunzio Crimi: None declared, Stefano Del Giacco: None declared, Allyson Egan: None declared, Georgina Espigol-Frigole Consultant of: Roche and Janssen, Mara Felicetti: None declared, Marco Folci: None declared, Paolo Fraticelli: None declared, Marcello Govoni: None declared, Anna Kernder Grant/research support from: Grant/research support from: GlaxoSmithKline and UCB Pharma for performing the LuLa-study., Carlo Lombardi: None declared, Giuseppe Lopalco: None declared, Claudio Lunardi: None declared, Aladdin J Mohammad Speakers bureau: lecture fees from Roche and Elli Lilly Sweden, PI (GiACTA study), Frank Moosig: None declared, Simone Negrini: None declared, Thomas Neumann: None declared, Pavel Novikov Grant/research support from: This work was supported by the 5-100 Project, Sechenov University, Moscow, Giuseppe Paolazzi: None declared, paola parronchi: None declared, Luca Quartuccio Consultant of: Abbvie, Bristol, Speakers bureau: Abbvie, Pfizer, Vito Racanelli: None declared, Carlo Salvarani: None declared, Maxime Samson: None declared, Jan Schroeder: None declared, Savino Sciascia: None declared, Renato A. Sinico: None declared, Benjamin Terrier: None declared, Paola Toniati: None declared, Domenico Prisco: None declared, Augusto Vaglio: None declared, Giacomo Emmi: None declared

This study aimed to evaluate the role of interleukin (IL)-1 inhibitors anakinra (ANA) and canakinumab (CAN) in the treatment of Behcet’s disease (BD)-related uveitis. Multicenter retrospective observational study includes 19 consecutive BD patients (31 affected eyes) received treatment with anti-IL-1 agents. Data were analyzed at baseline and at 3 and 12 months. The primary endpoint is the reduction of ocular inflammatory flares (OIF). The secondary endpoints are improvement of best corrected visual acuity (BCVA); reduction of macular thickness defined by optical coherence tomography (OCT) and of vasculitis identified with fluorescein angiography (FA); evaluation of statistically significant differences between patients treated with IL-1 inhibitors as monotherapy, subjects also administered with disease modifying anti-rheumatic drugs (DMARDs) and/or corticosteroids as well as between patients administered with IL-1 inhibitors as first line biologic treatment and those previously treated with TNF-α inhibitors. At 12 months, OIF significantly decreased from 200 episodes/100 patients/year to 48.87 episodes/100 patients/year (p

Background and Objective: Only a few studies have reported long-term efficacy of interleukin (IL)-1 inhibition in systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still disease (AOSD). Herein we report on the effectiveness of anakinra (ANA), expressed in terms of drug retention rate (DRR), and evaluate the predictive factors of drug survival in a cohort of patients with sJIA and AOSD. Patients and Methods: This is a multicenter study reviewing retrospectively the medical records from 61 patients with sJIA and 76 with AOSD, all treated with ANA in 25 Italian tertiary referral centers. Results: The cumulative retention rate of ANA at 12-, 24-, 48-, and 60-month 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 with the subgroup coadministered with conventional diseasemodifying antirheumatic drugs (cDMARDs) (p = 0.473). On the other hand, a significant difference in DRR was found between biologic-naïve patients and those previously treated with biotechnologic drugs (p = 0.009), which persisted even after adjustment for pathology (p = 0.013). In the regression analysis, patients experiencing adverse events (AEs) {hazards ratio (HR) = 3.029 [confidence interval (CI) 1.750–5.242], p < 0.0001} and those previously treated with other biologic agents [HR = 1.818 (CI 1.007–3.282), p = 0.047] were associated with a higher HR of ANA discontinuation. The median treatment delay was significantly higher among patients discontinuing ANA (p < 0.0001). Significant corticosteroid-sparing (p = 0.033) and cDMARD-sparing effects (p < 0.0001) were also recorded. Less than one-third of our cohort developed AEs, and 85% were deemed mild in nature, with 70% of them involving the skin. Conclusions: Our findings display an overall excellent DRR of ANA on the long run for both sJIA and AOSD, that may be further optimized by closely monitoring patient’s safety issues and employing this IL-1 inhibitor as a first-line biologic as early as possible. Moreover, ANA allowed a significant drug-sparing effect and showed an overall good safety profile.

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.

The prevalence of sarcopenia in rheumatic diseases has been evaluated in single diseases using various diagnostic approaches, generating conflicting data on the pathogenetic mechanism(s). Herein, we evaluated both muscle mass index (MMI) and muscle strength to assess sarcopenia and presarcopenia in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). Moreover, we evaluated the possible impact of disease/patient-related characteristics, therapeutic regimens, and nutritional aspects on sarcopenia. The present study included 168 patients of both genders, aged 40&ndash, 75 years. All patients underwent a nutritional evaluation, physical activity level assessment, rheumatologic evaluation, and an MMI and muscle strength assessment. The prevalence of sarcopenia was about 20% in all the three rheumatologic diseases, whereas presarcopenia was significantly different in RA, PsA and AS (p = 0.006). At multivariate analysis, only age &ge, 60 years and the presence of a disability were associated with a significantly increased risk of sarcopenia (p = 0.006 and p = 0.01, respectively), while a higher C-reactive protein did not reach statistical significance. Sarcopenia is similar in RA, PsA and AS, whereas presarcopenia significantly differs in these three diseases. Disease activity/inflammation and nutritional aspects do not influence sarcopenia, while age &ge, 60 years and the presence of a disability significantly increase the risk of sarcopenia.

Objective. This study was aimed at assessing the long-term ocular control of adalimumab (ADA) in a large real-world population with noninfectious primary or secondary uveitis, focusing on the steroid-sparing effect and on disease-modifying antirheumatic drug (DMARD) cotreatment. Methods. In this retrospective, multicenter study, the efficacy of ADA was evaluated in terms of ocular control, changes in best-corrected visual acuity (BCVA), corticosteroid-sparing effect, and drug retention rate, overall and stratified according to DMARD cotreatment. Results. 106 patients were included. 88.7% had an associated systemic disease. After 6 and 12 months, proportions of patients with effective ocular control were 83.7% and 83.3%, respectively. At last the follow-up, 94.6% of patients had satisfactory ocular control. No difference in terms of ocular control at all time points emerged among patients starting ADA for ocular vs. systemic involvements. Patients with poor baseline BCVA remained stable or improved, while those with good BCVA hardly worsened. At 6 and 12 months, the median dose of prednisone significantly reduced to 5 mg/day (0-5) and 2.5 mg/day (0-5) (p<0.001). Over a median follow-up of 36 months, 38 subjects discontinued ADA treatment. Mild to moderate side effects were reported in 7 patients (6.6%). ADA ocular control, corticosteroid-sparing effect, and drug retention rate were not influenced by the concomitant use of DMARDs. Conclusion. The long-term ocular control of ADA in noninfectious primary or secondary uveitis is confirmed, also for BCVA preservation. Concomitant use of DMARDs does not provide additional benefits to ADA alone in terms of ocular control, steroid spare, and drug retention rate.

Monogenic autoinflammatory disorders (AIDs) are rare diseases driven by cytokine-mediated extraordinary sterile inflammation that results from the activation of innate immune pathways. The clinical hallmark of these diseases is the recurrence of stereotyped episodes of systemic- and organ-specific inflammation; the most common systems involved being the skin, musculoskeletal system, gastrointestinal tract, and central nervous system. The autoinflammatory disorders may have a profound impact on the quality of life of the affected patients, and a delayed diagnosis may lead to severe complications, the most dreadful of which is AA-Amyloidosis. This review gives an overview on the four main AIDs, namely familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, cryopyrinopathies, and mevalonate kinase deficiency, focusing on their clinical phenotype in adults and differential diagnosis, suggesting a diagnostic algorithm, and reviewing the available treatments.

Behçet's syndrome (BS) is a systemic inflammatory disorder characterized by a wide range of potential clinical manifestations with no gold-standard therapy. However, the recent classification of BS at a crossroads between autoimmune and autoinflammatory syndromes has paved the way to new further therapeutic opportunities in addition to anti-tumor necrosis factor agents.This review provides a digest of all current experience and evidence about pharmacological agents recently described as having a role in the treatment of BS, including interleukin (IL)-1 inhibitors, tocilizumab, rituximab, alemtuzumab, ustekinumab, interferon-alpha-2a, and apremilast.IL-1 inhibitors currently represent the most studied agents among the latest treatment options for BS, proving to be effective, safe and with an acceptable retention on treatment. However, since BS is a peculiar disorder with clinical features responding to certain treatments that in turn can worsen other manifestations, identifying new treatment options for patients unresponsive to the current drug armamentarium is of great relevance. A number of agents have been studied in the last decade showing changing fortunes in some cases and promising results in others. The latter will potentially provide their contribution for better clinical management of BS, improving patients' quality of life and long-term outcome.

There is raising interest in the scientific community about the impact of body mass on different rheumatologic diseases. A growing body of evidence suggests that the effect of obesity on joint structure goes beyond the simply overload but is based on a complex interwinding of cytokines, hormones, growth factors, and intracellular regulators that at different stages can modify the course of a rheumatologic disease and the clinical response to biotherapies. In these settings, psoriatic arthritis (PsA) and rheumatoid arthritis (RA) have been the more extensively studied. Intriguing is the finding that the interaction between obesity and diseases seems different for PsA or RA. Concerning PsA, epidemiologic studies have provided robust data about the association between obesity and prevalence of psoriasis or PsA. Yet obesity is associated with an increase in degree of disability and poor clinical outcome on treatment with anti-tumor necrosis factor (TNF) drugs. Nevertheless, there are clues suggesting that weight reduction above 5% from baseline increases the probability of achieving a good clinical response in PsA patients on anti-TNF drugs. On the contrary, the epidemiological association between obesity and RA seems to be restricted to some categories of patients with peculiar demographic and autoimmune status. Furthermore, obesity definitely impairs the clinical response of RA patients to anti-TNF treatment, and this might be an effect limited to TNF-blocking agents, as preliminary studies are not confirming these findings for abatacept or tocilizumab. However, the most puzzling aspect of the impact of obesity on RA is that obese patients tend to have a more clinical active disease, an impaired response to biotherapies, and a less radiographically evident joint damage over time. The latter is a very stimulating issue and the knowledge of the underlying mechanisms should be an auspicious challenge for the researchers, which will provide further insights on the overall management of RA.

Multiple sclerosis (MS) is a chronic demyelinating disorder of central nervous system (CNS) leading to neurological disability. A wide variety of ophthalmic and neuro-ophthalmic manifestations have been associated with MS. Although this link is well recognized, controversial is still the risk of developing MS in patients with ophthalmic manifestations. Intermediate uveitis followed by panuveitis are the most common manifestations among the ophthalmic involvement in MS. Timely management of uveitis, is a crucial step to prevent irreversible visual impairment. A multidisciplinary team including ophthalmologists together with other specialists is required in the majority of cases for an adequate diagnostic and therapeutic approach of uveitis. Corticosteroids represent the mainstay of therapy in the acute phase, whereas conventional immunosuppressive drugs such as azathioprine may allow a steroid sparing effect. Increasing evidence from anti-CD 20 monoclonal antibodies such as rituximab have proven the efficacy on clinical and radiological outcomes in MS, on the contrary anti-Tumor Necrosis Factor (TNF) monoclonal antibodies such as infliximab and adalimumab are contraindicated in patients with demyelinating disorders, as they seem to worsen disease and neurological clinical symptoms. On this basis, MS-associated uveitis may deeply influence the therapeutic choices suggesting targeting inflammatory cytokines different from TNF. Recently, interleukin (IL)-1 blockade has been investigated as possible therapeutic tool in several inflammatory eye conditions such as Behcet's disease related uveitis, strengthening that IL-1 is also critical for the development of uveitis. Herein, we report our experience in a HLA-B27 positive patient with MS-associated uveitis successfully treated with the short-acting IL-1 receptor antagonist anakinra.

We thank Agca and colleagues1 for their valuable comments on our correspondence ‘Influence of changes in cholesterol levels and disease activity on the 10-years cardiovascular risk estimated with different algorithms in rheumatoid arthritis patients’.2 They highlighted the complexity of cardiovascular (CV) risk assessment in patients with rheumatoid arthritis (RA), with some aspects that need to be clarified. The purpose of our study was not to determine if possible changes in CV risk scores during the first 6 months of treatment with biologic agents reflect reality, for which we need, as suggested, much larger cohorts, but rather to evaluate how the changes in disease activity and lipid levels may differently impact on CV risk algorithms commonly used by physicians in their daily clinical practice. In our RA cohort we selected all patients who started a first-line biologic agent since January 2010 with all available data …

This review aims to summarize the role of the interleukin-1 (IL-1) blocking agents in cardiovascular diseases, briefly describing the pathogenetic rationale and the most relevant clinical studies. IL-1 is a pivotal cytokine of the innate immune system. Anti-IL-1 agents are currently used for the treatment of several autoimmune and autoinflammatory conditions. Recently, the role of IL-1 has also emerged in cardiovascular diseases. Indeed, two recent randomized controlled trials have shown that the IL-1 receptor antagonist anakinra is effective for the treatment of idiopathic recurrent pericarditis and the IL-1β blocking agent canakinumab is effective in reducing myocardial infarction in people at risk. Interestingly, interfering with IL-1 has proved to be also effective in other cardiovascular manifestations, such as myocarditis, arrhythmias, and heart failure. Blocking the IL-1 pathway is a possible new therapeutic strategy, potentially leading to innovative therapies in many acute and chronic cardiovascular diseases.

Background High-grade inflammation in patients affected with Rheumatoid Arthritis (RA) leads to an imbalanced body composition characterised by increased fat mass and decreased lean mass, with stable or increased body weight, resulting in little or no change in body mass index (BMI).1 This condition, known as rheumatoid cachexia, is proven to be reversible once inflammatory process has been shut down. BMI and waist-to-hip ratio (WHR) are used as indirect measurements of visceral fat even if not capable of discriminating it from subcutaneous fat tissue. An alternative method proposed for assessment of fat composition, indicating nutritional status, is bioelectrical impedance analysis (BIA). Objectives To analyse body fat composition of patients with RA assessed using either BIA and anthropometric measures, investigating relationships between the related indices, serum adipokines and disease activity. Methods The body composition of 87 consecutive patients (72 female, 82.76%) affected with RA according to 2010 ACR/EULAR classification criteria, mean age of 52.42±13.29, mean disease duration of 10.71±8.58 years, treated with DMARDs and/or biologics, was assessed during their visit to our outpatient department. Data including demographic characteristics clinical manifestations, disease activity indices (DAS28-ESR, DAS28-CRP, CDAI, SDAI), Health Assessment Questionnaire (HAQ), lipid profile, as well as radiological findings were collected. Patients underwent to anthropometric measures (WHR and BMI) and BIA for the evaluation of fat-free mass (FFM), fat mass (FM) and the derived indices (fat-free mass index (FFMI) and fat mass index (FMI)). In addition for each patient blood samples were collected to determine serum levels of several adipokines (leptin, adiponectin, visfatin, resistin). Statistical tests as well as linear and logistic regression analysis were carried out. Results DAS28-ESR was found to be related to FMI (p=0.02; r=0.22) and to BMI (p=0.03; r=0.22). In addition, in patients in whom DAS28-ESR remission was not achieved, FMI but not BMI was found to be related to the latter disease activity index (p=0.007, r=0.37). FMI was shown to correlate to HAQ (p=0.01, r=0.31). Higher serum levels of leptin were found to predict higher FMI and BMI (p Conclusions Either body fat composition assessed with BIA-related indices and serum leptin have been noticed to predict disease activity. Moreover nutritional status of patients in remission according to DAS28-ESR may be better assessed by determining indices brought by BIA along with BMI, in order to rule out rheumatoid cachexia on the basis of FMI and FFMI. Reference [1] Ferraz-Amaro I, Gonzalez-Juanatey C, Lopez-Mejias R, Riancho-Zarrabeitia L, Gonzalez Gay MA. Metabolic syndrome in rheumatoid arthritis. Mediators Inflamm2013. Disclosure of Interest None declared

The primary aim of the study was to evaluate the efficacy of tumor necrosis factor (TNF)-α blockers adalimumab (ADA) and infliximab (IFX) in refractory sight-threatening retinal vasculitis (RV) during a 12-month follow-up period. Secondary aims were to evaluate (i) any impact of concomitant conventional disease-modifying anti-rheumatic drugs (cDMARDs) and different lines of biologic therapy; (ii) any difference in terms of efficacy between ADA and IFX; (iii) consequences of biotherapies on the best-corrected visual acuity (BCVA); (iv) corticosteroid-sparing effect; and (vi) ocular complications during anti-TNF-α treatment. Demographic, clinical, and therapeutic data were retrospectively collected from the medical records and statistically analyzed. Forty-eight patients (82 eyes) were recruited, 22 (45.8%) of which received IFX and 26 (54.2%) ADA. The percentages of patients achieving RV remission within 3 and 12 months were 54 and 86%, respectively. A significant decrease in RV detection was identified from baseline to 3-month (p 0.0001) and 12-month (p 0.0001) assessments and between 3-month and 12-month visits (p = 0.004). No differences were identified in terms of RV resolution between (i) patients undergoing monotherapy and those co-administered with cDMARDs at 3-month (p = 0.560) and 12-month (p = 0.611) follow-up; (ii) biologic-naïve patients and those already exposed to other biologics at 3-month (p = 0.497) and 12-month (p 0.99) visits; and (iii) patients treated with ADA and those treated with IFX (p = 0.357). During the study period, a statistically significant corticosteroid-sparing effect was observed (p = 0.0002), while BCVA values did not significantly change (p = 0.950). Anti-TNF-α monoclonal antibodies have proved excellent results in patients with recalcitrant sight-threatening RV.

AIM To assess the impact of baseline modified Rheumatic Disease Comorbidity Index (mRDCI) a simple comorbidity count, on overall survival of treatments with biological drugs in patients affected with Rheumatoid Arthritis (RA), Spondyloarthritis (SpA) and Psoriatic Arthritis (PsA) in real-world settings. METHODS Patients (nr. 635) with RA (nr. 214), SpA (nr. 213) and PsA (nr. 208) starting a first biological drug were retrospectively analysed. mRDCI was scored at baseline, and disease characteristics were recorded at entry and at last observation. Drug retention was analysed using Kaplan-Meier curves. Cox regression models were used to estimate the association of baseline mRDCI with drug discontinuation and clinical outcomes, the achievement of clinical remission based on 28 joint-Disease Activity Score (DAS28)

To identify clinical variables capable of predicting long-term treatment duration of TNF-α inhibition in patients with Behcet's disease (BD)-related uveitis. Demographic, clinical, and therapeutic data were retrospectively collected from BD patients treated with the tumor necrosis factor (TNF)-α blockers infliximab and adalimumab. Patients still continuing TNF-α inhibitors at 48-month follow-up visits were classified as long-term responders and were statistically compared to patients discontinuing treatment before the 48-month visit. Forty-five patients (75 eyes) were enrolled. Thirty-two patients continued anti-TNF-α treatment for more than 48 months; 13 patients discontinued the treatment after a mean time of 12.3 ± 10.44 months due to lack (61.5%) or loss (38.5%) of efficacy. Baseline value of BD current activity form was the only variable discriminating long- and short-term responsive patients (p = 0.048, OR = 0.656, C.I. 95% 0.433-0.996). Disease activity levels at the start of treatment predict duration of response to monoclonal TNF antagonists in ocular BD.

Background/aimsAdalimumab (ADA) has been shown to be an effective treatment for Behçet’s disease (BD)-related uveitis. We aimed at evaluating the cumulative retention rate of ADA during a 48-month follow-up period in patients with BD-related uveitis, the impact of a concomitant use of disease modifying anti-rheumatic drugs (DMARDs) on ADA retention rate, and differences according to the various lines of biologic therapy (ie, first- vs second-line or more). Predictive factors of response to ADA were also investigated.MethodsWe enrolled patients diagnosed with BD-related uveitis and treated with ADA between January 2009 and December 2016. Cumulative survival rates were studied using the Kaplan-Meier plot, while the log-rank (Mantel-Cox) test was used to compare survival curves. Statistical analysis was performed to identify differences according to the response to ADA.Results54 consecutive patients (82 eyes) were eligible for analysis. The drug retention rate at 12- and 48-month follow-up was 76.9% and 63.5%, respectively. No statistically significant differences were identified according to the use of concomitant DMARDs (p=0.27) and to the different lines of ADA treatment (p=0.37). No significant differences were found between patients continuing and discontinuing ADA in terms of age (p=0.24), age at BD onset (p=0.81), age at uveitis onset (p=0.56), overall BD duration (p=0.055), uveitis duration (p=0.46), human leucocyte antigen-B51 positivity (p=0.51), and gender (p=0.47).ConclusionsADA retention rate in BD-related uveitis is excellent and is not affected by the concomitant use of DMARDs or by the different lines of biological therapy. Negative prognostic factors for BD uveitis do not impact ADA efficacy.

Purpose: To identify factors associated with sustained response to interleukin (IL)-1 inhibition among demographic, clinical and therapeutic data in patients with Behcet disease (BD).Method...

Recurrent pericarditis is one of the most frequent pericardial diseases, affecting up to 30% of the patients who have experienced acute pericarditis. While the diagnosis of acute pericarditis is sometime straight forward, its etiology and therapeutic management are still a challenge for physicians. In developed countries, the idiopathic form is the most frequent, and the search for an infectious etiology is almost invariably negative. Nevertheless, since standard treatment with nonsteroidal anti-inflammatory drugs and colchicine is not always able to neutralize pericardial inflammation in recurrent pericarditis, anakinra, an IL-1 receptor antagonist, has been proposed as a possible therapeutic alternative for refractory forms. IL-1 is a cytokine that exerts a pivotal role in innate immunity and in the pathogenesis of some autoimmune diseases, such as rheumatoid arthritis, and in autoinflammatory disorders, as familial Mediterranean fever and cryopyrin-associated periodic syndromes. The successful management of patients with acute idiopathic recurrent pericarditis (IRP) needs a teamwork approach, where cardiologists, rheumatologists, clinical immunologists and internists are involved. In this review, we will discuss the clinical and therapeutical challenges of IRP both in adults and children from a clinical practice standpoint. We will also briefly illustrate the main pathogenic mechanisms of IRP to provide internists and cardiologists with the rationale for approaching the use of anakinra in selected clinical cases.

Rheumatoid arthritis (RA) patients are at high risk of cardiovascular (CV) events, and the chronic inflammatory state may generate quantitative and qualitative changes in lipoprotein fractions. The anti-IL-6 receptor tocilizumab (TCZ), even if effective in inflammation and joint damage prevention, determined significant alterations to RA patients’ lipid levels in randomized controlled trials, but real-world data are lacking. We evaluated the changes in lipid fraction levels and disease activity in a longitudinal cohort of RA patients on long-term treatment with tocilizumab (TCZ) in a community setting. We retrospectively selected 40 naïve-biologic RA patients on treatment with intravenous TCZ compared to 20 RA patients on methotrexate treatment as the control group. Total cholesterol (Tot-Chol), low-density lipoproteins (LDL), high-density lipoprotein (HDL), and triglyceride (TG) levels were measured at the baseline and at 12, 24, and 52 weeks thereafter. At the same points, 28-joint disease activity score (DAS28), clinical disease activity index (CDAI), and EULAR clinical responses were also assessed. During the first 24 weeks, we observed in TCZ-treated patients a progressive statistically significant (p<0.001) increase in Tot-Chol, LDL, HDL, and TG, which returned close to the baseline at 52 weeks. But no changes in the lipid-related CV risk indices Tot-Chol/HDL and LDL/HDL ratios and the atherogenic index (log10 TG/HDL) were detectable. Notably, we observed a statistically significant negative correlation between changes in lipid fractions and DAS28 or CDAI. The prolonged treatment with TCZ was associated to a transient increase in cholesterol’s fractions during the first 6 months of treatment, with inverse correlation to disease activity, but with no impact on surrogate lipid indices of atherogenic risk. These findings may aid clinicians in interpreting the RA patient’s lipid profile in daily clinical practice.

Intraocular inflammation is one of the more relevant complications of Behçet's disease (BD), which tends to respond poorly to different medications. The ocular histopathologic changes are basically identical to those occurring in other organs and consist in a necrotizing leukocytoclastic obliterative vasculitis, which is probably immune complex-mediated and affects both arteries and veins of all sizes. There are growing evidences showing the potential role of biologic agents other than anti-tumor necrosis factor (TNF)-α agents in the management of ocular-BD, which have been collected in this review, including interleukin-1 and interleukin-6 blockade, secukinumab, ustekinumab, daclizumab, rituximab, and alemtuzumab. Further large studies are needed to fully elucidate and establish the clinical efficacy of these different tools in the refractory ocular manifestations of BD.