Effectiveness and Safety of Biosimilars in Pediatric Non-infectious Uveitis: Real-Life Data from the International AIDA Network Uveitis Registry

IntroductionSince many biological drug patents have expired, biosimilar agents (BIOs) have been developed; however, there are still some reservations in their use, especially in childhood. The aim of the current study is to evaluate the efficacy and safety of tumor necrosis factor (TNF) inhibitors BIOs as treatment for pediatric non-infectious uveitis (NIU).MethodsData from pediatric patients with NIU treated with TNF inhibitors BIOs were drawn from the international AutoInflammatory Disease Alliance (AIDA) registries dedicated to uveitis and Behcet's disease. The effectiveness and safety of BIOs were assessed in terms of frequency of relapses, risk for developing ocular flares, best-corrected visual acuity (BCVA), glucocorticoids (GCs)-sparing effect, drug survival, frequency of ocular complications, and adverse drug event (AE).ResultsForty-seven patients (77 affected eyes) were enrolled. The BIOs employed were adalimumab (ADA) (89.4%), etanercept (ETA) (5.3%), and infliximab (IFX) (5.3%). The number of relapses 12 months prior to BIOs and at last follow-up was 282.14 and 52.43 per 100 patients/year. The relative risk of developing ocular flares before BIOs introduction compared to the period following the start of BIOs was 4.49 (95% confidence interval [CI] 3.38-5.98, p = 0.004). The number needed to treat (NNT) for ocular flares was 3.53. Median BCVA was maintained during the whole BIOs treatment (p = 0.92). A significant GCs-sparing effect was observed throughout the treatment period (p = 0.002). The estimated drug retention rate (DRR) at 12-, 24-, and 36-month follow-up were 92.7, 83.3, and 70.8%, respectively. The risk rate for developing structural ocular complications was 89.9/100 patients/year before starting BIOs and 12.7/100 patients/year during BIOs treatment, with a risk ratio of new ocular complications without BIOs of 7.1 (CI 3.4-14.9, p = 0.0003). Three minor AEs were reported.ConclusionsTNF inhibitors BIOs are effective in reducing the number of ocular uveitis relapses, preserving visual acuity, allowing a significant GCs-sparing effect, and preventing structural ocular complications.Trial RegistrationClinicalTrials.gov ID NCT05200715

Musculoskeletal manifestations in children with Behçet's syndrome: data from the AIDA Network Behçet's Syndrome Registry

This study aims to describe musculoskeletal manifestations (MSM) in children with Behçet's syndrome (BS), their association with other disease manifestations, response to therapy, and long-term prognosis. Data were retrieved from the AIDA Network Behçet's Syndrome Registry. Out of a total of 141 patients with juvenile BS, 37 had MSM at disease onset (26.2%). The median age at onset was 10.0 years (IQR 7.7). The median follow-up duration was 21.8 years (IQR 23.3). Recurrent oral (100%) and genital ulcers (67.6%) and pseudofolliculitis (56.8%) were the most common symptoms associated with MSM. At disease onset, 31 subjects had arthritis (83.8%), 33 arthralgia (89.2%), and 14 myalgia (37.8%). Arthritis was monoarticular in 9/31 cases (29%), oligoarticular in 10 (32.3%), polyarticular in 5 (16.1%), axial in 7 (22.6%). Over time, arthritis became chronic-recurrent in 67.7% of cases and 7/31 patients had joint erosions (22.6%). The median Behçet's Syndrome Overall Damage Index was 0 (range 0-4). Colchicine was inefficacious for MSM in 4/14 cases (28.6%), independently from the type of MSM (p = 0.46) or the concomitant therapy (p = 0.30 for cDMARDs, p = 1.00 for glucocorticoids); cDMARDs and bDMARDs were inefficacious for MSM in 6/19 (31.4%) and 5/12 (41.7%) cases. The presence of myalgia was associated with bDMARDs inefficacy (p = 0.014). To conclude, MSM in children with BS are frequently associated with recurrent ulcers and pseudofolliculitis. Arthritis is mostly mono- or oligoarticular, but sacroiliitis is not unusual. Prognosis of this subset of BS is overall favorable, though the presence of myalgia negatively affects response to biologic therapies. ClinicalTrials.gov Identifier: NCT05200715 (registered on December 18, 2021)

Development and implementation of the AIDA International Registry for patients with Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis syndrome

Objective: Aim 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. Methods: This 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. Results: A 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. Conclusions: The 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 NCT 05200715

Development and Implementation of the AIDA International Registry for Patients with Non-Infectious Uveitis

Introduction: 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). Methods: 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. Results: 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. Conclusions: 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

Burnout among surgeons before and during the SARS-CoV-2 pandemic: an international survey

Background: SARS-CoV-2 pandemic has had many significant impacts within the surgical realm, and surgeons have been obligated to reconsider almost every aspect of daily clinical practice. Methods: This is a cross-sectional study reported in compliance with the CHERRIES guidelines and conducted through an online platform from June 14th to July 15th, 2020. The primary outcome was the burden of burnout during the pandemic indicated by the validated Shirom-Melamed Burnout Measure. Results: Nine hundred fifty-four surgeons completed the survey. The median length of practice was 10 years; 78.2% included were male with a median age of 37 years old, 39.5% were consultants, 68.9% were general surgeons, and 55.7% were affiliated with an academic institution. Overall, there was a significant increase in the mean burnout score during the pandemic; longer years of practice and older age were significantly associated with less burnout. There were significant reductions in the median number of outpatient visits, operated cases, on-call hours, emergency visits, and research work, so, 48.2% of respondents felt that the training resources were insufficient. The majority (81.3%) of respondents reported that their hospitals were included in the management of COVID-19, 66.5% felt their roles had been minimized; 41% were asked to assist in non-surgical medical practices, and 37.6% of respondents were included in COVID-19 management. Conclusions: There was a significant burnout among trainees. Almost all aspects of clinical and research activities were affected with a significant reduction in the volume of research, outpatient clinic visits, surgical procedures, on-call hours, and emergency cases hindering the training. Trial registration: The study was registered on clicaltrials.gov "NCT04433286" on 16/06/2020

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

ENT manifestations of Granulomatosis with polyangiitis

Ear, nose, and throat (ENT) symptoms represent the most frequent manifestations at the onset of granulomatosis with polyangiitis (GPA). The diagnosis of the localized form of GPA remains challenging thus contributing to the delay at the beginning of treatment. This could lead to major sequelae due to tissue destruction. Otolaryngologists play a key role in collaboration with rheumatologists in early GPA diagnosis and treatment. Clinicians should maintain a high index of suspicion and proceed to a more comprehensive evaluation in cases of imperfect response to treatment or with unexplained atypical findings. The challenging issue in localized organ involvement during GPA is to determine whether the non-specific local upper aerodigestive symptoms are caused by a specific or a non-specific inflammatory process. The role of surgery becomes crucial in cases of laryngeal involvement. Life-threatening airway compromise necessitates urgent surgical intervention. There is an emerging role in the local ENT therapies

Subcutaneous formulation of belimumab in treatment of systemic lupus erythematosus: a critical review with focus on safety and satisfaction

Belimumab is a novel add-on therapy that has been approved for patients with active and antibody-mediated systemic lupus erythematosus. It is a monoclonal antibody that decreases the activation of B-cells and consequently decreases antibodies\u27 production. Recently, the US Food and Drug Administration approved subcutaneous belimumab for patients who have received training on using it. Subcutaneous belimumab can be administered using either a prefilled syringe or an auto-injector device. Weekly subcutaneous belimumab seems to be as effective as monthly intravenous belimumab with a similar safety margin. In this article, we reviewed the literature on subcutaneous belimumab focusing on safety and patients\u27 experiences and satisfaction. Overall, subcutaneous belimumab appears to be preferred over intravenous belimumab for a number of reasons. However, more studies are still required to prove these findings

The impact of HCV eradication using interferon-free direct acting antivirals on bone-mineral, anemia parameters and peripheral insulin resistance in hepatitis c-infected Egyptian hemodialysis cohort

Abstract Background Hepatitis C virus (HCV) infection is linked to a higher mortality rate in hemodialysis (HD) patients. We aimed to see if HCV eradication using interferon-free direct acting antivirals (DAAs) can affect bone-mineral and anemia biochemical parameters such as serum calcium (Ca++), phosphorus (PO4 +), parathormone (PTH), fibroblast growth factor 23 (FGF23), hemoglobin (HB), and ferritin in HD patients and also peripheral insulin resistance by monitoring serum fasting insulin and HOMA insulin resistance (HOMA-IR). Methods Three hundred and thirty-four adults on regular HD with positive HCV genotype 4 (191 male and 143 female) were included; 157 of them had seroconversion during HD. All were hepatitis B virus (HBV) negative and received treatment with DAAs. All cases were examined for body mass index (BMI), HB, ferritin level, transferrin saturation (TSAT), Ca++, PO4 +, PTH, FGF23, serum albumin, alanine transaminase (ALT), fasting insulin level, and HOMA-IR at the beginning and then were measured after 6 and 12 months from a sustained virological response (SVR). Results After 6 and 12 months from SVR, there was a significant increase in serum Ca despite no change in oral calcium dose requirement over that period (p = 0001), a significant increase in HB, serum iron (p = 0001), and a significant reduction in serum ferritin, PO4, PTH, and FGF23 (p = 0001). Both fasting insulin level and HOMA-IR were statistically significantly dropped. Conclusion HCV eradication with interferon-free DAAs showed a statistically significant impact on hemodialysis patients regarding hemoglobin, ferritin level, bone-mineral parameters, and improvement in peripheral insulin resistance

Relapse of HCV-Cryoglobulinemic Vasculitis Following Sustained Viral Response after Interferon-free Direct-Acting Antivirals

Objectives: Direct-acting antiviral agents (DAAs) have modified the management of chronic hepatitis C virus (HCV) infection, including HCV-related cryoglobulinemia vasculitis (CryoVas). However, patients might experience vasculitis relapse, and no reliable predictors of CryoVas relapse following sustained virological response (SVR) have been established. We aimed to describe HCV-CryoVas relapse rates and factors associated with it. Methods: International multicenter cohort where patients with HCV-CryoVas from Egypt, France and Italy treated with DAA were analyzed retrospectively. Factors associated with relapse-free survival were evaluated in a multivariate adjusted model. Results: Out of 913 patients, 911 (99.8%) obtained SVR. After 35 months of median follow-up, 798 patients (87.4%) had sustained remission of vasculitis, while 115 (12.6%) experienced CryoVas relapse. By the time of relapse, skin involvement was present in 100%, renal involvement in 85.2%, and peripheral neuropathy in 81.7%. Relapses were treated with glucocorticoids in 90.9%, associated with plasma exchange, cyclophosphamide or rituximab in 50%, 37.3% and 6.4%, respectively. The cumulative incidence of CryoVas relapse was 0.7% (95%CI 0.3;1.4), 12.3% (95%CI 10.2;14.6) and 13.1% (95%CI 11.0;15.5) at 12, 24 and 36 months after DAA treatment, respectively. Independent baseline risk factors associated with CryoVas relapse were male sex, skin ulcers and kidney involvement at baseline and peripheral neuropathy at the end of DAA treatment. Death occurred in 11 relapsers, mainly due to infections. Conclusions: A substantial proportion of CryoVas patients experience relapse after DAA-induced SVR. Relapses are moderate-to-severe, and impact survival after 24 months, mainly due to infections. Independent risk factors for relapse or death were found