Development and Role in Therapy of Canakinumab in Adult-Onset Still's Disease

Adult-onset Still's disease (AOSD) is a rare inflammatory disease of unknown etiology typically characterized by episodes of spiking fever, evanescent rash, arthralgia, leukocytosis, and hyperferritinemia. The pivotal role of interleukin (IL)-1 and other pro-inflammatory cytokines gives rise to the development of new targeted therapies. Currently, AOSD patients can benefit from efficient and well tolerated biologic agents, such as IL-1, IL-6, and tumour necrosis factor (TNF)-\u3b1 antagonists. Canakinumab, a human monoclonal anti-IL-1\u3b2 antibody, is indicated for the treatment of different autoinflammatory syndromes in adults, adolescents, and children and it has recently been approved for AOSD treatment. In this article, we summarize the structural and biochemical data describing the molecular interactions between Canakinumab and its target antigen. Some special considerations of the pharmacological properties of Canakinumab are included. We also review the safety, efficacy and tolerability of this drug for the treatment of AOSD

Prevalence of low back pain and its effect on health-related quality of life in 409 scholar adolescents from the veneto region

Low back pain (LBP) is a common condition with profound effects on well-being. We aimed to define the prevalence and the characteristics of LBP and to investigate its impact on the quality of life (QoL) of 409 students (265 females and 144 males), all high-school adolescents from the Veneto region. LBP was measured with a structured, self-report questionnaire, while the SF-36 questionnaire was used to measure physical and mental QoL. 253 students (61.3%) reported one or more episodes of LBP, with female predominance. Adolescents with LBP treated with drugs and rehabilitation cares have significantly poor belief in pain resolution (p=0.005), but more belief in a prevention program (p=0.006) than the others. After adjustment for sex, a significant association between the SF-36 dimension of vitality and the presence of LBP in males was observed. All SF-36 domains except mental health were significantly higher in females with LBP. Our study confirmed that LBP is frequent in Italian scholar adolescents and has an impact on QoL. Strategies for reducing the effects of LBP on QoL should be an important purpose for clinicians and health policy makers

The role of architectural design for rheumatic patients' wellbeing: the point of view of Environmental Psychology

Rheumatic diseases (RD) are among the most frequent disorders in the population and the major causes of chronic pain and disability. The resulting consequences are catastrophic, leading to a significant socio-economic burden, which includes significant reductions in quality of life (QoL) and limitations in regular work and daily activities of patients. In spite of this, rheumatic diseases are often misunderstood or diagnosed late, probably due to their characteristics of silent diseases, sometimes unrecognizable to unaffected or unskilled people. Actually, it is surprising that, despite their consequences on QoL and on individual impact, rheumatic diseases are underestimated by the public opinion, which is probably more attracted by other major diseases causing death. This silent perception can even be seen in some among the most recent psycho-social approaches to population needs in the fields of Health Psychology and Environmental Psychology. The latter, also known as Architectural Psychology, is a branch of Psychology that analyses the effects of the built environment on humans, including those affected by diseases. Paradoxically, in many cases, some components of the environments created to protect individuals and/or the population may represent barriers and subsequently causes of disability and suffering in patients with rheumatic diseases. In order to increase awareness about this particular aspect of social life, HEMOVE Onlus, a non-profit association, has promoted the creation of a multidisciplinary Task Group, which included mainly rheumatologists, psychologists and architects, with the aim of applying also for the benefit of rheumatic patients the most modern technical skills available in the context of Environmental Psychology, including in particular design and information technology

Proteomics of rimmed vacuoles define new risk allele in inclusion body myositis

OBJECTIVE: Sporadic inclusion body myositis (sIBM) pathogenesis is unknown; however, rimmed vacuoles (RVs) are a constant feature. We propose to identify proteins that accumulate within RVs. METHODS: RVs and intact myofibers were laser microdissected from skeletal muscle of 18 sIBM patients and analyzed by a sensitive mass spectrometry approach using label-free spectral count-based relative protein quantification. Whole exome sequencing was performed on 62 sIBM patients. Immunofluorescence was performed on patient and mouse skeletal muscle. RESULTS: 213 proteins were enriched by >1.5X in RVs compared to controls and included proteins previously reported to accumulate in sIBM tissue or when mutated cause myopathies with RVs. Proteins associated with protein folding and autophagy were the largest group represented. One autophagic adaptor protein not previously identified in sIBM was FYCO1. Rare missense coding FYCO1 variants were present in 11.3% of sIBM patients compared with 2.6% of controls (p=0.003). FYCO1 co-localized at RVs with autophagic proteins such as MAP1LC3 and SQSTM1 in sIBM and other RV myopathies. One FYCO1 variant protein had reduced co-localization with MAP1LC3 when expressed in mouse muscle. INTERPRETATION: This study used an unbiased proteomic approach to identify RV proteins in sIBM that included a novel protein involved in sIBM pathogenesis. FYCO1 accumulates at RVs and rare missense variants in FYCO1 are overrepresented in sIBM patients. These FYCO1 variants may impair autophagic function leading to RV formation in sIBM patient muscle. FYCO1 functionally connects autophagic and endocytic pathways supporting the hypothesis that impaired endolysosmal degradation underlies the pathogenesis of sIBM

A Snapshot on the On-Label and Off-Label Use of the Interleukin-1 Inhibitors in Italy among Rheumatologists and Pediatric Rheumatologists: A Nationwide Multi-Center Retrospective Observational Study.

Background: Interleukin (IL)-1 inhibitors have been suggested as possible therapeutic options in a large number of old and new clinical entities characterized by an IL-1 driven pathogenesis. Objectives: To perform a nationwide snapshot of the on-label and off-label use of anakinra (ANA) and canakinumab (CAN) for different conditions both in children and adults. Methods: We retrospectively collected demographic, clinical, and therapeutic data from both adult and pediatric patients treated with IL-1 inhibitors from January 2008 to July 2016. Results: Five hundred and twenty-six treatment courses given to 475 patients (195 males, 280 females; 111 children and 364 adults) were evaluated. ANA was administered in 421 (80.04%) courses, CAN in 105 (19.96%). Sixty-two (32.1%) patients had been treated with both agents. IL-1 inhibitors were employed in 38 different indications (37 with ANA, 16 with CAN). Off-label use was more frequent for ANA than CAN (p < 0.0001). ANA was employed as first-line biologic approach in 323 (76.7%) cases, while CAN in 37 cases (35.2%). IL-1 inhibitors were associated with corticosteroids in 285 (54.18%) courses and disease modifying anti-rheumatic drugs (DMARDs) in 156 (29.65%). ANA dosage ranged from 30 to 200 mg/day (or 1.0-2.0 mg/kg/day) among adults and 2-4 mg/kg/day among children; regarding CAN, the most frequently used posologies were 150mg every 8 weeks, 150mg every 4 weeks and 150mg every 6 weeks. The frequency of failure was higher among patients treated with ANA at a dosage of 100 mg/day than those treated with 2 mg/kg/day (p = 0.03). Seventy-six patients (14.4%) reported an adverse event (AE) and 10 (1.9%) a severe AE. AEs occurred more frequently after the age of 65 compared to both children and patients aged between 16 and 65 (p = 0.003 and p = 0.03, respectively). Conclusions: IL-1 inhibitors are mostly used off-label, especially ANA, during adulthood. The high frequency of good clinical responses suggests that IL-1 inhibitors are used with awareness of pathogenetic mechanisms; adult healthcare physicians generally employ standard dosages, while pediatricians are more prone in using a weight-based posology. Dose adjustments and switching between different agents showed to be effective treatment strategies. Our data confirm the good safety profile of IL-1 inhibitors

Progress in Biological Therapies for Adult-Onset Still’s Disease

Adult-onset Still’s disease (AOSD) is a rare multifactorial autoinflammatory disorder of unknown etiology, characterized by an excessive release of cytokines triggered by dysregulated inflammation and articular and systemic manifestations. The clinical spectrum of AOSD ranges from self-limiting forms with mild symptoms to life-threatening cases and presents clinical and biological similarities with the juvenile form (sJIA). Nowadays, the advances in biologic agents no longer limit the treatment to NSAIDs, glucocorticoids, or conventional synthetic DMARDs. The blockade of IL-1 and IL-6 is effective in the treatment of systemic and articular inflammation of AOSD patients; however, novel compounds with different properties and targets are now available and others are being studied. In this review, starting from the pathogenesis of AOSD, we summarized the current and emerging biological therapies, possible effective agents for achieving AOSD control and remission

SAT0557 RESIDUAL DISEASE ACTIVITY IN ADULT-ONSET STILL'S DISEASE: QUALITATIVE AND QUANTITATIVE ANALYSIS OF A SERIES OF 18F FDG-PET/MR

Background:Adult-onset Still's disease (AOSD) is a systemic autoinflammatory disorder characterized by episodes of spiking fever, the presence of an evanescent pink-salmon rash, arthritis/arthralgias, sore throat and increased inflammatory serum markers. The diagnosis is clinical and needs the exclusion of potential mimickers such as infections and lymphoproliferative disorders. Currently, a specific diagnostic test to assess the disease activity is not available.Objectives:To define the residual disease activity in AOSD and establish a possible response to therapy through18F-FDG PET/MR imaging technique.Methods:23 patients affected by AOSD and 24 controls underwent18F-FDG PET/MR between 2014 and 2018. A total of 5418F-FDG PET/MR were analysed. AOSD patients were diagnosed according to the Yamaguchi's criteria and were in follow-up at the Rheumatology Unit of Padova University Hospital. The controls were chosen among non-AOSD patients with a previous diagnosis of solid tumors (lymphomas excluded). Aqualitative analysisof PET/RM carried out by a Nuclear Medicine Specialist and asemiquantitative analysiscarried out by measuring SUVs-to-liver (Standardized Uptake Value) for spleen, bone marrow (BM), lymph nodes and pharynx were performed. A SUVmax BM/SUVmean liver higher than 2.09 was set up as significant area of uptake for each organ considered. This threshold was calculated by adding the standard deviation multiplied by 2 at the mean ratio between SUVmax BM and SUVmean liver of the control group. The Pouchot score for disease activity was calculated for each subject. The distribution of the variables was investigated by Shapiro-Wilk test. The analysis of the association between the variables was carried out using the Mann-Whitney U test.Results:AOSD patients present areas of focal18F-FDG uptake mainly in BM, lymph nodes, pharynx, spleen and salivary glands. Sites of uptake in spleen were found in 3.3% of PET/MR, in BM in 23.3%, in lymph nodes in 23.3% and in pharynx in 36.6% of PET/RM respectively. Eleven/thirty (47.8%) patients were defined as "positive" since the uptake was higher than liver, and twelve/thirty (52.2%) were defined as "negative" since the uptake was lower than liver, regardless of SUVs and clinical manifestations. A semi-quantitative analysis assessed whether the values of the SUVmax BM/liver were higher than the cut-off of 2.09 in "positive" PET/MR and lower in the "negative" ones and if the clinical manifestations were present or absent in agreement with the evaluation of SUVs for each patient. BM was found to be active (SUVmax ratio > of 2.09) in 7 out of 11 patients when the PET/MR was defined "positive", while only in 1 case out of 12 BM SUVmax was >2.09 when the exam was "negative". Clinical manifestations were present in 10 out of 11 AOSD with a "positive" scan and in 7 out of 11 with both a "positive" scan and a SUV max BM/liver >2.09. Clinical manifestations were present in 1 out of 12 patients with a "negative" scan, while in 10 out of 12 cases with both a negative scan and a SUV max BM/liver <2.09 were absent. Six patients repeated PET/MR during follow-up. The values of the SUVmax BM/liver significantly decreased after anti IL-1β treatment with anakinra. In two cases in which anakinra was deferred, the BM SUVmax values exceeded the cut-off of 2.09 despite the patients did not complain any symptom or inflammation markers increase.Conclusion:18F FGD-PET/MR could be able to evaluate the disease activity in AOSD when clinical manifestations and serum markers are not sufficient to establish it. The uptake on BM seems quite sensitive in pointing out the disease severity and in assessing the response to anti IL-1β therapy.18F PET/MR is an accurate and repeatable method, however further studies are required to validate its applicability in routinary clinical practice.Disclosure of Interests:None declare

Intravenous anakinra to curb cytokine storm in adult-onset Still's disease and in macrophage activation syndrome: A case series

Objective: Adult-onset Still's disease (AOSD) is an auto-inflammatory polygenic disorder, for which the diagnosis is essentially clinical. The exclusion of mimickers [such as common bacterial and viral infections, hematologic malignancies, and, more recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)] is necessary to confirm the diagnosis. Anti-interleukin (IL)-1 therapy is considered a treatment milestone for AOSD. Herein, we present a short series of newly-diagnosed AOSD or upcoming macrophage activation syndrome (MAS) cases who received intravenous (IV) anakinra, an IL-1 receptor blocker. Methods: Four patients with newly-diagnosed AOSD or upcoming MAS were treated with IV anakinra at the Rheumatology Unit of Padova University Hospital, Italy. We obtained informed consent from the patients for use of their cases and medical images for publication purposes. Results: All patients presented with AOSD or MAS during the COVID-19 pandemic, making diagnosis challenging due to similar immunological and clinical characteristics across both pathologies. All patients presented with hyperpyrexia and elevated inflammatory markers; two patients had a skin rash typically seen in AOSD. IV anakinra slowed down AOSD progression in all patients, prevented severe outcomes and mitigated the risk of multiorgan failure. All cases improved within 24hours of anakinra administration. Conclusion: We found that administration of anakinra in patients with newly-diagnosed AOSD and/or upcoming MAS reduced hyperinflammation and prevented life-threatening complications. The IV route appears to be preferable in the hospital setting, where comorbidities such as coagulopathies and thrombocytopenia can complicate the use of other routes of administration

The revisited role of interleukin-1 alpha and beta in autoimmune and inflammatory disorders and in comorbidities

The interleukin (IL) 1 family of cytokines is noteworthy to have pleiotropic functions in inflammation and acquired immunity. Over the last decades, several progresses have been made in understanding the function and regulation of the prototypical inflammatory cytokine (IL-1) in human diseases. IL-1\u3b1 and IL-1\u3b2 deregulated signaling causes devastating diseases manifested by severe acute or chronic inflammation. In this review, we examine and compare the key aspects of IL-1\u3b1 and IL-1\u3b2 biology and regulation and discuss their importance in the initiation and maintenance of inflammation that underlie the pathology of many human diseases. We also report the current and ongoing inhibitors of IL-1 signaling, targeting IL-1\u3b1, IL-1\u3b2, their receptor or other molecular compounds as effective strategies to prevent or treat the onset and progression of various inflammatory disorders