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

Introduction: Still’s disease is a systemic, non-monogenic autoinflammatory condition affecting both children and adolescents (systemic juvenile idiopathic arthritis, sJIA) and adults (adult-onset Still’s disease, AOSD). Its clinical spectrum ranges from mild forms to life-threatening cases. Glucocorticoids represent the first-line therapy, but their chronic use is burdened with significant side effects. Hence, add-on therapy with disease modifying anti-rheumatic drugs and biologic anti-cytokine agents is frequently required, especially in patients with severe and recalcitrant clinical phenotypes. Among the targetable cytokines with a primary role in the pathogenesis of Still’s disease, interleukin-1 has a leading position. Areas covered: This review presents the available controlled evidence and observational studies regarding the efficacy and safety of canakinumab, a monoclonal antibody targeting interleukin-1β, in the treatment of Still’s disease. Expert opinion: Controlled studies fully support the clinical efficacy of canakinumab in the treatment of patients affected by sJIA. Conversely, strong evidences are still lacking in AOSD patients; nevertheless, its use in the adult population is legitimated by an increasing number of cases series and case reports and by preclinical data linking the pathogenesis of these two diseases. In addition, canakinumab has an excellent safety profile. Its role in preventing and treating macrophage activation syndrome is still debated.

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.

Adult onset Still's disease (AOSD) is a rare systemic autoinflammatory disease, characterised by fever, arthritis, and skin rash, and joint involvement is one of its clinical manifestations. The aims of this work were to assess joint involvement, to describe main patterns of involvement, and associated clinical characteristics. In this work, we aimed at assessing the joint involvement in AOSD by using MRI, to describe main patterns and associated clinical characteristics. In addition, we aimed at assessing the global transcriptomic profile of synovial tissues in AOSD to elucidate possible pathogenic pathways involved. We also evaluated the global transcriptomic profile of synovial tissues to elucidate possible pathogenic pathways involved in the disease. Thus, AOSD patients, who underwent to MRI exam on joints, were assessed to describe patterns of joint involvement and associated clinical characteristics. Some synovial tissues were collected for RNA-sequencing purposes. The most common MRI finding was the presence of synovitis on 60.5%, mainly in peripheral affected joints, with low to intermediate signal intensity on T1-weighted images and intermediate to high signal intensity on T2-fat-saturated weighted and STIR images. Bone oedema and MRI-bone erosions were reported on 34.9% and 25.6% MRI exams, respectively. Patients with MRI-bone erosions showed a higher prevalence of splenomegaly, a more frequent chronic disease course, lower levels of erythrocyte sedimentation rate, and ferritin. In AOSD synovial tissues, a hyper-expression of interleukin (IL)-1, IL-6, and TNF pathways was shown together with ferritin genes. In conclusion, in AOSD patients, the most common MRI-finding was the presence of synovitis, characterised by intermediate to high signal intensity on T2-fat-saturated weighted and STIR images. MRI-bone erosions and bone oedema were also observed. In AOSD synovial tissues, IL-1, IL-6, and TNF pathways together with ferritin genes resulted to be hyper-expressed.

Background Adult-onset Still's disease (AOSD) is a systemic inflammatory disease of unknown etiology, lacking specific diagnosis and disease activity evaluation indicators. This study will analyze the activity and clinical significance of Adenosine deaminase (ADA) in AOSD patients. Methods Totally 53 AOSD patients, 60 patients with other autoimmune diseases including systemic lupus erythematosus (SLE), sjogren syndrome (SS) and rheumatoid arthritis (RA), as well as 60 healthy subjects were included in this study. AOSD activity was determined by Pouchot score. We analyzed the correlation between ADA activity and clinical parameters. In addition, the correlation between ADA activity and disease activity score was also analyzed. Results This study showed that the activity of ADA in AOSD patients was significantly higher than that of healthy controls, SLE, SS and RA patient groups (p p r = 0.54, p r = 0.82, p r = 0.67, p r = − 0.42, p = 0.002) and platelet counts (r = − 0.44, p = 0.001). We also found a significant positive correlation between the activity of ADA and Pouchot score in AOSD patients (r = 0.51, p = 0.001). Receiver operating characteristic (ROC) curve analysis showed that ADA activity had a sensitivity of 93.3%, and a specificity of 83% for the diagnosis of AOSD, with an area under the curve of 0.93. Conclusion This study showed that serum ADA activity can be used as a potential biomarker for AOSD diagnosis and disease activity assessment.

Background Adult-onset Still's disease (AOSD) is characterized by a classical triad of spiking fever, arthritis, and evanescent rash. It is one of the main causes of hospital admissions for fever of unknown origin and has an extended mean time to diagnosis. Therefore, it remains underdiagnosed relative to its aforementioned time frame. In this study, we attempt to highlight clinical and lab findings associated with AOSD. We then compare our diagnostic results with similar previous studies. Our results should help physicians not to miss this rare entity and make the diagnosis in a reduced time frame. Materials and methods This a retrospective, single-center study conducted at Dow University Hospital in Karachi, Pakistan. Thirty patients were enrolled in this study for six months (July 2019-December 2019). All patients were identified and recruited in the medical outpatient department using Yamaguchi's criteria. Written consent was obtained from all patients to access all their clinical charts. Demographics and prior results of laboratory investigations were retrieved from the chart files. Results In our study, the mean age of patients was 26.6 years. More specifically, males accounted for 53.3% (n=16) of cases, and females accounted for 46.6% (n=14) of total cases. The most common presenting clinical features included arthralgia (100%, n=30), fever (100%, n=30), myalgia (96.6%, n=29), large joint arthritis (66.6%, n=20), sore throat (50%, n=15), hepatomegaly (40%, n=12), splenomegaly (23.3%, n=7), skin rash (36.6%, n=11) and pericarditis (20%, n=6). Furthermore, none of our patients had cervical lymphadenopathy. The most commonly reported laboratory findings include leukocytosis (100%, n=30), hyperferritinemia (90%, n=27), elevated erythrocyte sedimentation rate (100%, n=30) and abnormal liver function tests (76.6%, n=23). Chest x-rays performed in all patients revealed no abnormalities in 83% of patients (n=25). All patients in our study sample (n=30) tested negative for antinuclear antibodies and rheumatoid factor. It was also noted that the mean duration of diagnosis in our patients was 5.98 weeks. The mean hospitalization period in our patients was 12.5 days. Furthermore, 16.7% of patients (n=5) suffered from disease relapse. Conclusion Our study ascertains that the presence of certain clinical and laboratory findings strongly indicate a diagnosis of adult-onset Still's disease.

Adult-onset Still's disease (AOSD) is a systemic inflammatory disease characterized by cytokine storm. However, a diagnostic test for AOSD in clinical use is yet to be validated. The aim of our study was to identify non-invasive biomarkers with high specificity and sensitivity to diagnosis of AOSD. MicroRNA (miRNA) profiles in PBMC from new-onset AOSD patients without any treatment and healthy controls (HCs) were analyzed by miRNA deep sequencing. Plasma samples from 100 AOSD patients and 60 HCs were used to validated the expression levels of miRNA by qRT-PCR. The correlations between expression levels of miRNAs and clinical manifestations were analyzed using advanced statistical models. We found that plasma samples from AOSD patients showed a distinct miRNA expression profile. Five miRNAs (miR-142-5p, miR-101-3p, miR-29a-3p, miR-29c-3p, and miR-141-3p) were significantly upregulated in plasma of AOSD patients compared with HCs both in training and validation sets. We discovered a panel including 3 miRNAs (miR-142-5p, miR-101-3p, and miR-29a-3p) that can predict the probability of AOSD with an area under the receiver operating characteristic (ROC) curve of 0.8250 in training and validation sets. Moreover, the expression levels of 5 miRNAs were significantly higher in active AOSD patients compared with those in inactive patients. In addition, elevated level of miR-101-3p was found in AOSD patients with fever, sore throat and arthralgia symptoms; the miR-101-3p was also positively correlated with the levels of IL-6 and TNF-α in serum. Furthermore, five miRNAs (miR-142-5p, miR-101-3p, miR-29c-3p, miR-29a-3p, and miR-141-3p) expressed in plasma were significantly higher in AOSD patients than in sepsis patients (P < 0.05). The AUC value of 4-miRNA panel (miR-142-5p, miR-101-3p, miR-29c-3p, and miR-141-3p) for AOSD diagnosis from sepsis was 0.8448, revealing the potentially diagnostic value to distinguish AOSD patients from sepsis patients. Our results have identified a specific plasma miRNA signature that may serve as a potential non-invasive biomarker for diagnosis of AOSD and monitoring disease activity.

Adult-onset Still’s disease (AOSD) is a known cause of fever of unknown origin. It is characterized by a triad of symptoms: spiking fever (>39°C), salmon-colored rash and arthritis/arthralgia. On a predisposing genetic background, several conditions may act as trigger for disease and among these, infectious agents are the most important. Nowadays, a dichotomous view of AOSD has been introduced which distinguishes this entity in two subsets according to the clinical features and laboratory aspects: systemic or articular. As AOSD is a diagnosis of exclusion, specific biomarkers able to facilitate differential diagnosis are needed. A number of possible biomarkers have been proposed that will be discussed in detail in this review: ferritin, IL-18, procalcitonin, s100 proteins and sCD163.

TNFAIP3 encodes the NF-κB regulatory protein A20. High-penetrance heterozygous mutations in TNFAIP3 cause a haploinsufficiency of A20 (HA20), inadequate inhibition of NF-κB pathway, and an early onset autoinflammatory disorder. However, the clinical phenotype of patients with HA20 varies greatly and clinical diagnoses prior to establishing the genetic cause, included both autoimmune and autoinflammatory conditions. Here, we present the first patient with HA20, who was previously diagnosed with AOSD but was later found to have a novel heterozygous variant in TNFAIP3 and who was successfully treated with anti-IL6 receptor biologic tocilizumab (RoActemra). We discovered a novel heterozygous mutation in TNFAIP3 c.1906C>T, not previously found in ExAC database. Further analysis shows that this single-nucleotide variant at the terminal residue of TNFAIP3 exon 7 produces an alternatively spliced mRNA resulting in p.His636fsTer1. Additional genetic analysis of family members shows that this variant does segregate with the inflammatory clinical phenotypes. Subsequent functional test show that NF-κB activation, measured as intracellular phosphorylation of p65 in CD14 + monocytes, was more enhanced in the patient compared with healthy controls (HC) following stimulation with LPS. This was associated with higher production of inflammatory cytokines by the patients PBMC in response to LPS and ATP and enhanced activation of NLRP3 inflammasome complex. Furthermore, increased activation of NLRP3 inflammasome was evident systemically, since we detected higher levels of ASC specks in patients’ sera compared with HC. Finally, we used population genetics data from GnomAD to construct a map of both genetic conservation and most probable disease-causing variants in TNFAIP3 which might be found in future cases of HA20.

A 34 year-old Afro-Caribbean female presented with recurring episodes of fever and lower abdominal pain over a period of two months not improving despite courses of antibiotics for possible recurrent urinary tract infections. On admission to hospital, patient was treated for a possible pyelonephritis or pelvic inflammatory disease (PID). Extensive investigations into possible source of infection were carried out. However, all of the repeated microbiological cultures were normal. Patient was investigated further for other possible causes including connective tissue disease, haematological disorders, or neoplasm, all of which were normal. Diagnosis of adult onset Still’s disease (AOSD) was confirmed by a rheumatologist based on Yamaguchi’s diagnostic criteria for AOSD alongside significantly raised serum ferritin. Patient was treated with steroids to which she showed remarkable clinical improvement alongside marked reduction in her serum ferritin levels. LEARNING POINTS The four giant causes of fever of unknown origin are: infections, connective tissue diseases, haematological disorders, and malignancies. AOSD is a diagnosis of exclusion using Yamaguchi criteria alongside raised ferritin levels (the most sensitive biomarker). Most AOSD patients will respond to steroid treatment. However, approximately one third of the patients require further immunosuppression to achieve disease remission.

Model-Driven Architecture is an approach which tackles such problems as: the high availability that a software product requires to be ready for use, the high degree of evolution that a software system has nowadays, etc. However, in the development of large complex systems, the benefits of that approach have been diminished due to the size and complexity of models that describe these kinds of systems. At this point Aspect-Oriented Software Development (AOSD) appears to improve the understanding, reusability and adaptation of the software artefacts. Its mechanism is based on modularization of crosscutting concerns in well-identified isolated entities called aspects. For this reason we propose to use together AOSD and MDA in the hope of reducing the shortcomings of the latter. Thus, aspects like security, replication, real-time constraints, etc., will be modelled by specialist modellers independently throughout the MDA framework. Our proposal exploits a tool for checking the consistency between different models (aspects) at the same level of abstraction; supporting the traceability of UML elements, requirements, and concerns; and controlling the impact of changes throughout the MDA framework.

This paper presents MView, a technique that enables the separation of various architect views on an architectural connector in distributed software systems. A distributed system faces a lot of variability in the functions that it needs to support, and the deployment environments in which it needs to execute. Modularity of functionality and composition is essential in achieving this variability. While state-of-the-art AO-ADLs focus on describing compositions using aspect-based connectors, there is no support for describing a connector across multiple architecture views. This is, however, essential for distributed systems, where run-time and distribution characteristics are represented in multiple views. This results in connectors that suffer from monolithic descriptions, in which the views of different architects are tangled. MView untangles these architect views by defining them in separate modules and specifying refinement relations between these modules. We have integrated MView in an ADL, called MViewADL, which is supported by an Eclipse-plugin that performs code generation to the JBoss and Spring middleware platforms. We evaluate MView in a content distribution system for e-Media. First is an assessment of the architect effort required for creating variations of that system, followed by an evaluation of the extent to which changes ripple through the architecture. ispartof: pages:109-147 ispartof: LNCS Transactions on Aspect-Oriented Software Development vol:7800 pages:109-147 ispartof: 11th Annual Aspect-Oriented Software Development Conference location:GERMANY, Hasso Plattner Inst, Potsdam date:25 Mar - 30 Mar 2012 status: published

Companies offering software services to external customer organizations must ensure that the non-functional requirements of all these customer organizations are satisfied. However, in such a cross-organizational context where services are provided and consumed by different organizations, the implementation of features, for example security, is scattered across the services of the different organizations and cannot be condensed into a single module that is applicable to multiple services. In this paper we present an aspect-based coordination architecture for dynamic composition of cross-organizational features in distributed software systems such as systems of systems or service supply chains. The underlying approach of this architecture is to specify the features at a higher level that abstracts the internal mechanism of the organizations involved. A coordination middleware dynamically integrates the appropriate features into the service composition, driven by metadata-based user preferences. In this paper we present an aspect-based coordination architecture for dynamic composition of cross-organizational features in distributed software systems such as systems of systems or service supply chains. The underlying approach of this architecture is to improve existing aspect-based composition technology by leveraging some of the principles of cross-org coordination architectures. Features, supporting for example security, can be automatically and dynamically integrated driven by metadata-based user preferences. ispartof: pages:183-197 ispartof: Distributed Applications and Interoperable Systems vol:6115 pages:183-197 ispartof: IFIP international conference on Distributed Applications and Interoperable Systems (DAIS) location:Amsterdam, The Netherlands date:7 Jun - 9 Jun 2010 status: published

With the maturation and widespread adoption of AOSD comes the need for patterns and best practices to solve recurring problems. Such patterns have been documented in different publications. Besides a conclusive catalog, a system to relate the patterns and drive the process of pattern selection would bear significant benefits. In this position paper, we designate the road towards a pattern language for aspect-based design and describe the initial steps. ispartof: pages:13-15 ispartof: PLATE '09: Proceedings of the 1st workshop on Linking aspect technology and evolution pages:13-15 ispartof: PLATE location:Charlottesville, Virginia, USA date:2 Mar - 6 Mar 2009 status: published

Systems software uses conditional compilation to manage crosscutting concerns in a very fine-grained and efficient way, but at the expense of tangled and scattered conditional code. Refactoring of conditional compilation into aspects gets rid of these issues, but it is not clear yet for which patterns of conditional compilation aspects make sense and whether or not current aspect technology is able to express these patterns. To investigate these two problems, this paper presents a graphical ``preprocessor blueprint'' model which offers a queryable representation of the syntactical interaction of conditional compilation and the source code. A case study on the Parrot VM shows that preprocessor blueprints are able to express and query for the four commonly known patterns of conditional compilation usage, and that they allow to discover seven additional important patterns. By correlating each pattern's potential for refactoring into advice and each pattern's evolution of the number of occurrences, we show that refactoring into advice in the Parrot VM is a good alternative for three of the eleven patterns, whereas for the other patterns trade-offs have to be considered between robustness and fine-grainedness of the advice.

In systems software, the C preprocessor is heavily used to manage variability and improve efficiency. It is the primary tool to model crosscutting concerns in a very fine-grained way, but leads to extremely tangled and scattered preprocessor code. In this paper, we explore the process of aspect mining and extraction in the context of preprocessor-driven systems. Our aim is to identify both opportunities (extracting conditional compilation into advice) and pitfalls (mining on unpreprocessed code) in migrating preprocessor code to aspects. We distill five trade-offs which give a first impression about the usefulness of replacing the preprocessor by aspects. Preprocessor-driven systems prove to be a real challenge for aspect mining, but they could become on the other hand one of the most promising applications of AOP.

Timeliness and criticality of a process are the two main concerns when designing real-time systems. In addition to that embedded systems are bounded by limited resources. To achieve these concerns while at the same time using a minimal amount or resources, real-time embedded systems use different techniques such as task scheduling, resource management and task synchronization. These techniques involve a number of the modules of the system which makes the use of Aspect-Oriented Software Development imperative. AOSD is a programming technique which uses the notion of join points to capture specific locations in code execution and then use advices to insert new code. This paper examines existing work in the development of schedulers, resource allocation agents and synchronization techniques using Aspect-Oriented Software Development in real-time embedded systems. An analysis of the existing research is used to describe the advantages of using AOSD over conventional OOP methods and to identify areas where further research may be required. ISAS 388 393 Sponsors: Cyprus Computer Society Conference code: 80774

Background Anakinra is the first interleukin-1 inhibitor to be used in clinical practice, and recent evidence showed that interleukin-1 plays a pivotal role in the pathogenesis of adult-onset Still disease (AoSD). However, data concerning efficacy with anakinra use in different clinical trials has not been evaluated, and the overall remission of AoSD with anakinra treatment has not been well defined. Methods We conducted a search on Embase, PubMed, and the Cochrane Library for relevant trials. Statistical analyses were conducted to calculate the overall remission rates, odds ratios (OR), and 95% confidence intervals (CI), by using either random effects or fixed effect models according to the heterogeneity. Results Of the 273 articles that were identified, 265 were excluded. Eight studies were eligible for inclusion. The overall remission rate and complete remission rate of anakinra in AoSD patients were 81.66% (95% CI: 69.51%–89.69%) and 66.75% (95% CI: 59.94%–75.3%), respectively. Compared with the controls, the use of anakinra was associated with a significant remission in AoSD, with an OR of 0.16 (95% CI: 0.06–0.44, P=0.0005). There were also significant reductions of the dosage of corticosteroid (mean difference =21.19) (95% CI: 13.2–29.18, P

Adult onset Still′s disease (AOSD) is a systemic inflammatory disorder of unknown etiology characterized by spiking fever, evanescent skin rash, arthralgia or arthritis, involvement of various organs, and predominantly neutrophilic leucocytosis. AOSD, although uncommon, has a characteristic constellation of clinical and laboratory features and should be considered in the differential diagnosis of pyrexia of unknown origin associated with a rash and arthralgia. The diagnosis is one of clinical suspicion and it is essential that infections, malignancy, and other rheumatic diseases are excluded. We report a case which illustrates the typical features of AOSD that were treated with steroids and azathioprine.

Virtual machine (VM) implementations are made of intricately intertwined subsystems, interacting largely through implicit dependencies. As the degree of crosscutting present in VMs is very high, VM implementations exhibit significant internal complexity. This study proposes an architecture approach for VMs that regards a VM as a composite of service modules coordinated through explicit bidirectional interfaces. Aspect-oriented programming techniques are used to establish these interfaces, to coordinate module interaction, and to declaratively express concrete VM architectures. A VM architecture description language is presented in a case study, illustrating the application of the proposed architectural principles.