Role of Proteasomes in Inflammation

The ubiquitin–proteasome system (UPS) is involved in multiple cellular functions including the regulation of protein homeostasis, major histocompatibility (MHC) class I antigen processing, cell cycle proliferation and signaling. In humans, proteasome loss-of-function mutations result in autoinflammation dominated by a prominent type I interferon (IFN) gene signature. These genomic alterations typically cause the development of proteasome-associated autoinflammatory syndromes (PRAAS) by impairing proteasome activity and perturbing protein homeostasis. However, an abnormal increased proteasomal activity can also be found in other human inflammatory diseases. In this review, we cast a light on the different clinical aspects of proteasomal activity in human disease and summarize the currently studied therapeutic approaches

Hemolytic anemia following intravenous immunoglobulins in children with PIMS-TS: Two case reports

This is the first case report on two children presenting with immediate and severe hemolytic anemia following the administration of high-dose intravenous immunoglobulins (IVIGs) in the context of pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS). Hemolytic anemia was described as a significant decrease in hemoglobin and an increase in lactate dehydrogenase after the second administration of high-dose IVIGs was performed. Both patients were found to have AB blood group. One of our patients showed massive pallor, weakness, and inability to walk in association with hemolysis. However, in both cases, the anemia was self-limiting and transfusion of red blood cells was not required: both patients recovered without persistent impact. Nonetheless, we aim to draw attention to this widely unknown adverse effect of IVIG, especially in the context of PIMS-TS. We suggest determining the patient's blood group prior to high-dose IVIG infusion and replacing the second IVIG through high-dose steroids or anticytokine therapy. Using IVIGs containing lower titers of specifically anti-A or anti-B antibodies to avoid isoagglutinin-caused hemolytic anemia is desirable; however, the information is not routinely available

Expression of ICOS In Vivo Defines CD4+ Effector T Cells with High Inflammatory Potential and a Strong Bias for Secretion of Interleukin 10

The studies performed to date analyzed the overall participation of the inducible costimulator (ICOS) in model diseases, but did not yield information on the nature and function of ICOS-expressing T cells in vivo. We examined ICOS+ T cells in the secondary lymphoid organs of nonmanipulated mice, in the context of an “unbiased” immune system shaped by environmental antigens. Using single cell analysis, ICOSlow cells were found to be loosely associated with the early cytokines interleukin (IL)-2, IL-3, IL-6, and interferon (IFN)-γ. ICOSmedium cells, the large majority of ICOS+ T cells in vivo, were very tightly associated with the synthesis of the T helper type 2 (Th2) cytokines IL-4, IL-5, and IL-13, and these cells exhibited potent inflammatory effects in vivo. In contrast, ICOShigh T cells were highly and selectively linked to the anti-inflammatory cytokine IL-10. Overall, these data seem to indicate that ICOS cell surface density serves as a regulatory mechanism for the release of cytokines with different immunological properties. Further in vivo functional experiments with in vitro–activated T cells strongly suggested that the ICOS+ population, although representing in vivo only around 10% of T cells bearing early or late activation markers, nevertheless encompasses virtually all effector T cells, a finding with major diagnostic and therapeutic implications

Juvenile arthritis caused by a novel FAMIN (LACC1) mutation in two children with systemic and extended oligoarticular course

Background The pathophysiological origin of juvenile idiopathic arthritis (JIA) is largely unknown. However, individuals with presumably pathogenic mutations in FAMIN have been reported, associating this gene with a rare subtype of this disorder. FAMIN, that is formerly also referred to as LACC1 or C13orf31, has recently been shown to play a crucial role in immune-metabolic functions and is involved in regulation of inflammasome activation and promotion of ROS production. Case presentation We describe two siblings with severe familial forms of juvenile arthritis in which whole-exome-sequencing revealed a novel homozygous frameshift mutation (NM_153218.2:c.827delC¸. p.(T276fs*2) in FAMIN. Conclusions The observation of a new deleterious mutation adds further evidence that pathogenic mutations in FAMIN are causal for a monogenic form of JIA. Furthermore the associated phenotype is not restricted to systemic JIA, but can also be found in other forms of familial juvenile arthritis

a comparative study with ultrasonography

Background Valid detection of arthritis is essential in differential diagnosis of joint pain. Indocyanin green (ICG)-enhanced fluorescence optical imaging (FOI) is a new imaging method that visualizes inflammation in wrist and finger joints. Objectives of this study were to compare FOI with ultrasonography (US, by gray-scale (GS) and power Doppler (PD)) and clinical examination (CE) and to estimate the predictive power of FOI for discrimination between inflammatory and non-inflammatory juvenile joint diseases. Methods FOI and GSUS/PDUS were performed in both hands of 76 patients with joint pain (53 with juvenile idiopathic arthritis (JIA), 23 with non-inflammatory joint diseases). Inflammation was graded by a semiquantitative score (grades 0–3) for each imaging method. Joints were defined clinically active if swollen or tender with limited range of motion. Sensitivity and specificity of FOI in three phases dependent on ICG enhancement (P1–P3) were analyzed with CE and GSUS/PDUS as reference. Results For JIA patients, FOI had an overall sensitivity of 67.3%/72.0% and a specificity of 65.0%/58.8% with GSUS/PDUS as reference; specificity was highest in P3 (GSUS 94.3%/PDUS 91.7%). FOI was more sensitive for detecting clinically active joints than GSUS/PDUS (75.2% vs 57.3%/32.5%). In patients with non-inflammatory joint diseases both FOI and US showed positive (i.e., pathological) findings (25% and 14% of joints). The predictive value for discrimination between inflammatory and non-inflammatory joint diseases was 0.79 for FOI and 0.80/0.85 for GSUS/PDUS. Conclusions Dependent on the phase evaluated, FOI had moderate to good agreement with CE and US. Both imaging methods revealed limitations and should be interpreted cautiously. FOI may provide an additional diagnostic method in pediatric rheumatology. Trial registration Deutsches Register Klinischer Studien DRKS00012572. Registered 31 July 2017

EULAR recommendations for the management of familial Mediterranean fever

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease, but many rheumatologists are not well acquainted with its management. The objective of this report is to produce evidence-based recommendations to guide rheumatologists and other health professionals in the treatment and follow-up of patients with FMF. A multidisciplinary panel, including rheumatologists, internists, paediatricians, a nurse, a methodologist and a patient representative, was assembled. Panellists came from the Eastern Mediterranean area, Europe and North America. A preliminary systematic literature search on the pharmacological treatment of FMF was performed following which the expert group convened to define aims, scope and users of the guidelines and established the need for additional reviews on controversial topics. In a second meeting, recommendations were discussed and refined in light of available evidence. Finally, agreement with the recommendations was obtained from a larger group of experts through a Delphi survey. The level of evidence (LoE) and grade of recommendation (GR) were then incorporated. The final document comprises 18 recommendations, each presented with its degree of agreement (0-10), LoE, GR and rationale. The degree of agreement was greater than 7/10 in all instances. The more controversial statements were those related to follow-up and dose change, for which supporting evidence is limited. A set of widely accepted recommendations for the treatment and monitoring of FMF is presented, supported by the best available evidence and expert opinion. It is believed that these recommendations will be useful in guiding physicians in the care of patients with FMF

Severe infections of Panton-Valentine leukocidin positive Staphylococcus aureus in children

Infections caused by Panton-Valentine leukocidin-positive Staphylococcus aureus (PVL-SA) mostly present as recurrent skin abscesses and furunculosis. However, life-threatening infections (eg, necrotizing pneumonia, necrotizing fasciitis, and osteomyelitis) caused by PVL-SA have also been reported.We assessed the clinical phenotype, frequency, clinical implications (surgery, length of treatment in hospitals/intensive care units, and antibiotic treatments), and potential preventability of severe PVL-SA infections in children.Total, 75 children treated for PVL-SA infections in our in- and outpatient units from 2012 to 2017 were included in this retrospective study.Ten out of 75 children contracted severe infections (PVL-methicillin resistant S aureus n = 4) including necrotizing pneumonia (n = 4), necrotizing fasciitis (n = 2), pyomyositis (n = 2; including 1 patient who also had pneumonia), mastoiditis with cerebellitis (n = 1), preorbital cellulitis (n = 1), and recurrent deep furunculosis in an immunosuppressed patient (n = 1). Specific complications of PVL-SA infections were venous thrombosis (n = 2), sepsis (n = 5), respiratory failure (n = 5), and acute respiratory distress syndrome (n = 3). The median duration of hospital stay was 14 days (range 5-52 days). In 6 out of 10 patients a history suggestive for PVL-SA colonization in the patient or close family members before hospital admission was identified.PVL-SA causes severe to life-threatening infections requiring lengthy treatments in hospital in a substantial percentage of symptomatic PVL-SA colonized children. More than 50% of severe infections might be prevented by prompt testing for PVL-SA in individuals with a history of abscesses or furunculosis, followed by decolonization measures

The German version of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR)

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the German language. The reading comprehension of the questionnaire was tested in 10 JIA parents and patients. The participating centres were asked to collect demographic and clinical data along the JAMAR questionnaire in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the three Likert assumptions, floor/ceiling effects, internal consistency, Cronbach\u2019s alpha, interscale correlations, test\u2013retest reliability, and construct validity (convergent and discriminant validity). A total of 319 JIA patients (2.8% systemic, 36.7% oligoarticular, 23.5% RF negative polyarthritis, and 37% other categories) and 100 healthy children were enrolled in eight centres. The JAMAR components discriminated well healthy subjects from JIA patients. All JAMAR components revealed good psychometric performances. In conclusion, the German version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and in clinical research

An International Delphi Survey for the Definition of the Variables for the Development of New Classification Criteria for Periodic Fever Aphtous Stomatitis Pharingitis Cervical Adenitis (PFAPA).

BACKGROUND: Diagnosis of Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) is currently based on a set of criteria proposed in 1999 modified from Marshall\u27s criteria. Nevertheless no validated evidence based set of classification criteria for PFAPA has been established so far. The aim of this study was to identify candidate classification criteria PFAPA syndrome using international consensus formation through a Delphi questionnaire survey. METHODS: A first open-ended questionnaire was sent to adult and pediatric clinicians/researchers, asking to identify the variables thought most likely to be helpful and relevant for the diagnosis of PFAPA. In a second survey, respondents were asked to select, from the list of variables coming from the first survey, the 10 features that they felt were most important, and to rank them in descending order from most important to least important. RESULTS: The response rate to the first and second Delphi was respectively 109/124 (88%) and 141/162 (87%). The number of participants that completed the first and second Delphi was 69/124 (56%) and 110/162 (68%). From the first Delphi we obtained a list of 92 variables, of which 62 were selected in the second Delphi. Variables reaching the top five position of the rank were regular periodicity, aphthous stomatitis, response to corticosteroids, cervical adenitis, and well-being between flares. CONCLUSION: Our process led to identification of features that were felt to be the most important as candidate classification criteria for PFAPA by a large sample of international rheumatologists. The performance of these items will be tested further in the next phase of the study, through analysis of real patient data

Recommendations for the management of autoinflammatory diseases.

Autoinflammatory diseases are characterised by fever and systemic inflammation, with potentially serious complications. Owing to the rarity of these diseases, evidence-based guidelines are lacking. In 2012, the European project Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate regimens for the management of children and young adults with rheumatic diseases, facilitating the clinical practice of paediatricians and (paediatric) rheumatologists. One of the aims of SHARE was to provide evidence-based recommendations for the management of the autoinflammatory diseases cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) and mevalonate kinase deficiency (MKD). These recommendations were developed using the European League Against Rheumatism standard operating procedure. An expert committee of paediatric and adult rheumatologists was convened. Recommendations derived from the systematic literature review were evaluated by an online survey and subsequently discussed at a consensus meeting using Nominal Group Technique. Recommendations were accepted if more than 80% agreement was reached. In total, four overarching principles, 20 recommendations on therapy and 14 recommendations on monitoring were accepted with ≥ 80% agreement among the experts. Topics included (but were not limited to) validated disease activity scores, therapy and items to assess in monitoring of a patient. By developing these recommendations, we aim to optimise the management of patients with CAPS, TRAPS and MKD