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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.

Juvenile psoriatic arthritis (JPsA) accounts for 1–7% of all cases of juvenile idiopathic arthritis (JIA) and its definition has been a matter of controversy among pediatric rheumatologists for many years. The traditional attribution of JPsA to the spondyloarthropathy group was challenged in the early 1990s, whereas the recent demonstrations of its heterogenous nature have led to questions about its identification as a distinct category in JIA classification. It has been shown that children with the phenotype of JPsA can be divided in two subgroups, one presenting with the features of early-onset ANA-positive JIA, and another that belongs to the spectrum of spondyloarthropathies. The few studies that have compared the clinical characteristics and genetic determinants of JPsA with those of the other JIA categories have obtained contrasting findings. The debate on the categorization of JPsA as a distinct entity within JIA classification is still ongoing and has prompted the revision of its current classification.

OBJECTIVE. To provide updated guidelines for pharmacologic management of juvenile idiopathic arthritis (JIA), focusing on treatment of oligoarthritis, temporomandibular joint (TMJ) arthritis, and systemic JIA with and without macrophage activation syndrome. Recommendations regarding tapering and discontinuing treatment in inactive systemic JIA are also provided. METHODS. We developed clinically relevant Patient/Population, Intervention, Comparison, and Outcomes questions. After conducting a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation approach was used to rate the quality of evidence (high, moderate, low, or very low). A Voting Panel including clinicians and patients/caregivers achieved consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS. Similar to those published in 2019, these JIA recommendations are based on clinical phenotypes of JIA, rather than a specific classification schema. This guideline provides recommendations for initial and subsequent treatment of JIA with oligoarthritis, TMJ arthritis, and systemic JIA as well as for tapering and discontinuing treatment in subjects with inactive systemic JIA. Other aspects of disease management, including factors that influence treatment choice and medication tapering, are discussed. Evidence for all recommendations was graded as low or very low in quality. For that reason, more than half of the recommendations are conditional. CONCLUSION. This clinical practice guideline complements the 2019 American College of Rheumatology JIA and uveitis guidelines, which addressed polyarthritis, sacroiliitis, enthesitis, and uveitis. It serves as a tool to support clinicians, patients, and caregivers in decision-making. The recommendations take into consideration the severity of both articular and nonarticular manifestations as well as patient quality of life. Although evidence is generally low quality and many recommendations are conditional, the inclusion of caregivers and patients in the decision-making process strengthens the relevance and applicability of the guideline. It is important to remember that these are recommendations. Clinical decisions, as always, should be made by the treating clinician and patient/caregiver.

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.

Objective To compare clinical features and treatments of patients with systemic JIA (sIJA) and adult-onset Still’s disease (AOSD). Methods The clinical charts of consecutive patients with sJIA by International League of Association of Rheumatology criteria or AOSD by Yamaguchi criteria were reviewed. Patients were seen at a large paediatric rheumatology referral centre or at 10 adult rheumatology academic centres. Data collected included clinical manifestations, inflammation biomarkers, systemic score, macrophage activation syndrome (MAS), parenchymal lung disease, disease course, disability, death and medications administered. Results A total of 166 patients (median age at diagnosis 5 years) with sJIA and 194 patients with AOSD (median age at diagnosis 41 years) were included. The frequency of fever, rash, arthralgia, abdominal pain, MAS, parenchymal lung disease and increased acute phase reactants and ferritin were comparable between the two cohorts. Patients with sJIA had a higher prevalence of arthritis, whereas patients with AOSD had experienced leucocytosis and extra-articular organ involvement more frequently. Patients with AOSD were given more commonly low-dose corticosteroids, whereas biologic DMARDs were administered first-line more frequently in patients with sJIA. Conclusion We found remarkable disparities in the prevalence of clinical manifestations between the two illnesses, which may partly depend on their classification by different criteria.

ObjectiveTo investigate the frequency in which the physician provides a global assessment of disease activity (PhGA) >0 and an active joint count (AJC)=0 in children with juvenile idiopathic arthritis (JIA) and search for determinants of divergence between the two measures.MethodsData were extracted from a multinational cross-sectional dataset of 9966 patients who had JIA by International League of Associations for Rheumatology criteria, were recruited between 2011 and 2016, and had both PhGA and AJC recorded by the caring paediatric rheumatologist at the study visit. Determinants of discordance between PhGA>0 and AJC=0 were searched for by multivariable logistic regression and dominance analyses.ResultsThe PhGA was scored >0 in 1647 (32.3%) of 5103 patients who had an AJC of 0. Independent associations with discordant assessment were identified for tender or restricted joint count >0, history of enthesitis, presence of active uveitis or systemic features, enthesitis-related or systemic arthritis, increased acute phase reactants, pain visual analogue scale (VAS)>0, and impaired physical or psychosocial well-being. In dominance analysis, tender joint count accounted for 35.43% of PhGA variance, followed by pain VAS>0 (17.72%), restricted joint count >0 (16.14%) and physical health score >0 (11.42%).ConclusionWe found that many paediatric rheumatologists did not mark a score of 0 for patients who they found not to have active joints. The presence of pain in joints not meeting the definition of active joint used in JIA was the main determinant of this phenomenon.

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.

Macrophage activation syndrome (MAS) is a serious, potentially life-threatening, hyperinflammatory condition, which belongs to the spectrum of hemophagocytic lymphohistiocytosis (HLH) and can complicate several immunologic and rheumatic disorders. MAS is characterized by a dysfunctional immune response that is similar to that seen in other forms of HLH. Because MAS may pursue a rapidly fatal course, prompt recognition of its clinical and laboratory features and immediate therapeutic intervention are fundamental. Recently, a set of classification criteria for MAS complicating sJIA has been developed through a multinational collaborative effort. High-dose parenteral corticosteroids remain the mainstay of treatment of MAS.

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.

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. Key Words: Celiac disease, Del22 syndrome, malabsorption

The family of type I cytokines, including IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, shares common transducing element the common cytokine receptor γc. The receptors containing γc exert prominent mitogenic effects and play an important role in several immunological functions and in supporting cell survival. The γc-dependent cytokine receptors use the Janus Kinase (JAK)/Signal transducer and activator of transcription (STAT) signaling pathway to mediate gene activation or repression. The Growth Hormone (GH) is a peptide of 191 amino acids and 22 kDa molecular weight, produced by the adenohypophysis, that regulates many important functions, as control of cellular metabolism, immune functions, fertility and somatic growth. Of note, the existence of a previously unappreciated functional interaction between γc and Growth Hormone receptor (GH-R) has been recently documented. The impairment of various GHinduced events in patients affected with severe combined immunodeficiencies due to γc defects suggests a potential functional interaction between GH-R pathways and γc, indicating a further link between endocrine and immune system with potential implication of the molecule in the cell cycle progression and control. GH-R pathways and γc interaction leads to the activation and intranuclear translocation of STAT5b protein. Moreover, evidence suggests that both GHinduced and spontaneous cell cycle progression and cell growth are strongly dependent on the amount of γc expression. To date, the regulation of cell survival and apoptosis can be considered a delicate teamwork and a proper functionality of γc-dependent cytokines on the whole seems to play prominent roles, as revealed by the profound impact that their abnormal function can have on the homeostasis of the immune system.

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.