Anterior Segment-Optical Coherence Tomography features in Blau syndrome.

Blau syndrome (BS) is a rare granulomatous auto-inflammatory disease, characterized by the classic clinical triad of joints, skin and ocular involvements. Ocular manifestation usually consists in a bilateral insidious chronic anterior uveitis with a potential evolution to panuveitis. We describe the case of two siblings, an 8-years old female and a 5-years old male, with a diagnosis of BS, evaluated by Anterior Segment-Optical Coherence Tomography (AS-OCT). In the female patient, slit-lamp examination revealed bilateral anterior granulomatous uveitis and inflammatory sequelae. AS-OCT revealed high intensity reflective layers in the anterior cornea, hyperreflective dots both in the aqueous humor and in the posterior corneal surface. In the male, no signs of inflammation were detected both on slit-lamp examination and AS-OCT scans. AS-OCT is a valuable, non-invasive tool that could improve the diagnosis of ocular involvement, better characterize and follow-up corneal alterations and anterior segment features in pediatric patients with BS

Increased relapse rate during COVID-19 lockdown in an Italian cohort of children with juvenile idiopathic arthritis.

Objectives: Changes of routine disease management associated with COVID-19 lockdown might have potentially affected the clinical course of juvenile idiopathic arthritis (JIA). Aim of our study was to assess the rate of disease flare before and during COVID-19 lockdown to investigate its impact on disease course in JIA children. Methods: A single-center retrospective study was conducted, including patients presenting inactive JIA between September 1st , 2018 and March 9th , 2019 (group A) and between September 1st , 2019 and March 9th , 2020 (group B). For each patient, demographic and clinical data were collected. The rate of JIA flare from March 10th , 2019 to June 30th , 2019 for group A and from March 10th , 2020 to June 30th , 2020 for group B was compared. Results: Group A included 126 patients and group B 124 patients. Statistical analysis did not show significant differences among the two cohorts with respect to age, sex, age of JIA onset, JIA subtype, co-occurrence of uveitis, ANA positivity and past or ongoing medications. The rate of disease flare during lockdown at time of first COVID-19 pandemic wave, was significantly higher in comparison to the previous year (16.9% vs 6.3%, p=0.009). Conclusion: Our study showed that COVID-19 lockdown was associated with a higher rate of joint inflammation in JIA children. This finding has a considerable clinical implication, since restrictive measures may be necessary in order to contain pandemics. Our data highlight the need for rearrangement in the home and healthcare management of JIA children during lockdowns

Gastrointestinal involvement in patients affected with 22q11.2 deletion syndrome

Objective. Enteropathy is a very common feature in patients with primary immunodeficiencies. In patients with Del22 gastrointestinal (GI) alterations, including feeding disorders and congenital abnormalities have been often reported, mostly in the first year of life. Material and methods. Aim of this monocentric study is to better define the GI involvement in a cohort of 26 patients affected with Del22 syndrome. Anamnestic information was retrospectively collected for each patient. Weight and height parameters at the time of the screening were recorded. Plasma levels of hemoglobin, iron, ferritin, albumin, total protein, calcium, phosphorus, transaminase levels, antigliadin (AGA) IgA and IgG, and antitissue transglutaminase (anti-TGase) titers were measured. Results. A GI involvement was identified in the 58% of patients. The prominent problems were abdominal pain, vomiting, gastroesophageal reflux and chronic constipation. Weight deficiency, short stature and failure to thrive were reported in 54, 42, and 30% of the patients, respectively. The evidence of sideropenic anemia, in keeping with hypoproteinemia, impaired acid steatocrit or cellobiose/mannitol test suggested an abnormal intestinal permeability. In this cohort, a high prevalence of AGA IgA and IgG positivity was observed. Celiac disease (CD) was suspected in three patients, and in one of them confirmed by histology. In this patient, a long-lasting gluten-free diet failed to restore the intestinal architecture. Conclusions. In conclusion, GI involvement is a very common feature in Del22 patients. A better characterization of GI involvement would be very useful to improve the management of these patients

Etanercept as a successful therapy in autoinflammatory syndrome related to TRNT1 mutations: a case-based review

Mutations in the gene encoding tRNA nucleotidyltransferase 1 (TRNT1) are associated with heterogeneous phenotypes and multisystem involvement of variable severity and progression. Immunodeficiency and inflammation are recurrent-associated features. The use of cytokine inhibitors in suppressing the inflammatory phenotype has been recently reported, with a 3-year follow-up for patients treated with Etanercept. We report on two unrelated patients sharing the same clinical condition, who had been referred to our Pediatric Rheumatology Unit because of recurrent fever associated with cutaneous lesions and increased levels of inflammatory markers since their first months of life. Whole exome sequencing allowed to identify compound heterozygosity for functionally relevant variants in TRNT1 as the only molecular event shared by the two patients. Both patients have been treated with Etanercept during 11 years, documenting normalization of inflammatory indexes and resolution of recurrent fever and associated symptoms. This is the longest follow-up assessment of Etanercept treatment in patients with TRNT1 mutations. Our findings confirm efficacy and safety of the treatment.Key Points• Mutations in TRNT1 have been associated with phenotypic heterogeneity.• We report on two patients with early-onset autoinflammatory syndrome.• Whole exome sequencing led to reveal compound heterozygosity for two variants in TRNT1 in both patients.• The patients were successfully treated with Etanercept for more than 10 years, the longest follow-up described in literature

Severe combined immunodeficiences: new and old scenarios

Severe combined immunodeficiencies (SCIDs) represent a group of distinct congenital disorders affecting either cell-mediated or humoral immunity, which lead invariably to severe and life-threatening infections. The different forms of SCID are currently classified according to the presence or absence of T, B, and NK cells. This greatly helps define the site of the blockage during the differentiation process. Even though SCID patients share common clinical features, such as opportunistic infections and failure to thrive, irrespective of the underlying pathogenetic mechanism, the discovery of new causative gene alterations led to identify novel complex clinical phenotypes, sometimes associated to extrahematopoietic manifestations. In a few cases, the presenting signs may be peculiar to that specific form and physicians should be alerted in recognizing such complex phenotypes, in order to avoid delay in the diagnostic procedures. The aim of this review is to alert care-givers to take into account also the less frequent clinical features and novel pathogenic mechanisms to direct the functional and molecular studies toward a certain genetic alteration

TLR9 signaling in patients with ectodermal dysplasia and immunodeficiency associated with Nuclear Factor Essential Modulator (NEMO) mutations

Background: Hypohidrotic ectodermal dysplasia (HED) is a group of disorders of ectodermal tissues, resulting from mutations in the ectodysplasin-A (EDA) pathway. Hypomorphic mutations in the NF-?B essential modulator (NEMO) result in HED with immunodeficiency (HED-ID, OMIM 300291), characterized by susceptibility to encapsulated bacteria, mycobacteria, and herpes virus infections. Objective: To analyze B-cell compartment and TLR9 signaling in HED-ID patients. Methods: Two HED-ID patients and a patient with HED caused by EDA gene mutation (XLHED) to confirm the implication of NFkB in this pathway were studied. Results: In HED-ID, differently from XLHED, only few B cells acquired the phenotype of IgM memory and differentiated into plasma cells upon TLR9 stimulation. Memory B cells did not produce IgG and IgA, and only small amounts of IgM in vitro. Conclusion: In HED-ID patients, TLR9 signaling is abnormal, in keeping with the lack of IgM memory B cells and natural antibodies. In individuals at a high risk of developing pneumococcal diseases, increased susceptibility to Streptococcus pneumonia infections and poor response to polysaccharide antigens have been associated with the lack of IgM memory B cells, required for the T-independent response toward encapsulated bacteria, whose differentiation from transitional B cells is under TLR9 control. This finding helps explain the susceptibility to infections by encapsulated bacteria

Space Adaptive Methods/Meshing

This chapter describes space adaptive approaches developed by six TILDA partners for the application in scale-resolving simulations. They are designed to provide sufficient spatial resolution in regions where required and to allow a lower resolution elsewhere for efficiency reasons. Adaptation techniques considered include mesh (h-refinement), order refinement of the spatial discretization (p-refinement) or a combination of both (hp-refinement). Furthermore, near-wall local mesh refinement, refinement using feature-based indicators and indicators obtained from the Variational Multiscale Method are considered

Canakinumab in systemic juvenile idiopathic arthritis: real-world data from a retrospective Italian cohort

Objective: The objective of this study was to use real-world data to evaluate the effectiveness and safety of canakinumab in Italian patients with systemic JIA (sJIA). Methods: A retrospective multicentre study of children with sJIA was performed. Clinical features, laboratory parameters and adverse events were collected at baseline, and 6 and 12 months after starting canakinumab. The primary outcome measure of effectiveness was clinically inactive disease (CID) off glucocorticoids (GCs) treatment at 6 months. Results: A total of 80 children from 15 Italian centres were analysed. Of the 12 patients who started canakinumab in CID while receiving anakinra, all maintained CID. Of the 68 with active disease at baseline, 57.4% achieved CID off GCs at 6 months and 63.8% at 12 months. In univariate analysis, the variables significantly related to non-response were number of active joints (NAJs) ≥5, history of macrophage activation syndrome (MAS) and disease duration. Multivariate analysis confirmed the association between non-response and NAJs ≥5 [odds ratio (OR) 6.37 (95% CI: 1.69, 24.02), P = 0.006] and between non-response and history of MAS [OR 3.53 (95% CI: 1.06, 11.70), P = 0.039]. No serious adverse events were recorded in this series. There were two cases of MAS during canakinumab, leading to a rate of 2.9 episodes per 100 patient years. Conclusion: We have confirmed, using real-world data, the efficacy of canakinumab in sJIA in a multicentric cohort. History of MAS and higher NAJ were associated with lower probability of achieving CID