The neural, the endocrine, and the immune systems are studied as distinct districts in physiological and pathological settings. However, these systems must be investigated with an integrative ...approach, while also considering that therapeutic agents, such as glucocorticoids, can induce a reversible or irreversible change of this homeostasis. Children and adolescents affected by rheumatic diseases frequently need treatment with corticosteroids, and the treatment must sometimes be continued for a long time. In the biological era, the treat-to-target strategy allowed a real revolution in treatment, with significant steroid dose sparing or, in many patients, steroid treatment withdrawal. In this review, the impact of glucocorticoids on endocrine, immune, and neurologic targets is analyzed, and the crosstalk between these systems is highlighted. In this narrative review, we explore the reasoning as to why glucocorticoids can disrupt this homeostasis, we summarize some of the key results supporting the impact of glucocorticoids treatment on endocrine, immune, and neurologic systems, and we discuss the data reported in the international literature.
To compare the long-term disease state, in terms of activity and damage, of children with juvenile idiopathic arthritis (JIA) who had their disease onset in methotrexate (MTX) or biologic eras.
...Patients were included in MTX or biologic era cohort depending on whether their disease presentation occurred before or after January 2000. All patients had disease duration ≥ 5 years and underwent a prospective cross-sectional assessment, which included measurement of disease activity and damage. Inactive disease (ID) and low disease activity (LDA) states were defined according to Wallace, JADAS10, and cJADAS10 criteria. Articular and extraarticular damage was assessed with the Juvenile Arthritis Damage Index (JADI).
MTX and biologic era cohorts included 239 and 269 patients, respectively. Patients were divided in the "functional phenotypes" of oligoarthritis and polyarthritis. At cross-sectional visit, patients in the biologic era cohort with either oligoarthritis or polyarthritis had consistently higher frequencies of ID and LDA by all criteria. The measurement of disease damage at cross-sectional visit revealed that the frequency of impairment of > 1 JADI-Articular items was higher in MTX than in biologic era cohort (17.6% versus 11% in oligoarthritis and 52.6% versus 21.8% in polyarthritis). Likewise, frequency of involvement of > 1 JADI-Extraarticular items was higher in the MTX than in the biologic era cohort (26.5% versus 16.2% in oligoarthritis and 31.4% versus 13.5% in polyarthritis).
Our study provides evidence of the remarkable outcome improvement obtained with the recent therapeutic advance in JIA.
Intra-articular venous malformations (IAVM) are rare benign vascular anomalies that usually affect young patients and most common locate in the knee. The terminology of these lesions is still ...ill-defined, as they are often termed in the literature as synovial hemangiomas. Early diagnosis can be difficult, because they usually present with nonspecific clinical manifestations that are similar those of other rheumatic diseases, especially juvenile idiopathic arthritis (JIA).
We conducted a retrospective analysis of five pediatric patients admitted to our units for recurrent swelling of the knee, and compared their characteristics with those of literature reports. The average age at first symptom and time from onset to diagnosis was 3.9 years (range 18 months-7 years) and 3.5 years (range 1-7 years), respectively. In our patients, an initial misdiagnosis of JIA, bleeding disorder or traumatic arthropathy was made. On MRI imaging, the features of the lesion were similar in all patients, and were marked by isointense-to-hypointense signal in T1-weighted images, and hyperintense signal in T2-weighted images. When performed, arthrocentesis led to aspiration of bloody fluid. The diagnosis was confirmed with a biopsy and histopathologic assessment in all patients. Open surgery enabled complete excision of the mass and was followed by stable remission over time in all cases.
Our report highlights the challenges that may be posed by the detection of knee IAVM and the frequent long delay between onset of symptoms and diagnosis. The key elements for early recognition include careful assessment of patient history, demonstration of bloody fluid on arthrocentesis, and proper interpretation of MRI scanning.
One of the most intriguing and mysterious phenomena observed during the COVID-19 pandemic has been represented by the occurrence of the multisystem inflammatory syndrome in children and adolescents ...(MIS-C). Patients with this condition have some overlapping signs and symptoms with those of Kawasaki disease (KD), but also display clinical features that are uncommon or less frequent in this illness, such as diarrhea, abdominal pain and myocardial involvement. The sickest patients may develop multiorgan failure and shock, usually due to myocarditis. Management is based on the administration of intravenous immunoglobulin, glucocorticoids and, in the most severe instances, anakinra. It is still debated whether MIS-C and KD represent different illnesses or are part of the same disease spectrum. The aim of the present review is to analyze critically the evidence in favor of the latter hypothesis and to provide the authors' personal interpretation of the relationship between the two conditions.
New early low-invasive biomarkers are demanded for the management of Oligoarticular Juvenile Idiopathic Arthritis (OJIA), the most common chronic pediatric rheumatic disease in Western countries and ...a leading cause of disability. A deeper understanding of the molecular basis of OJIA pathophysiology is essential for identifying new biomarkers for earlier disease diagnosis and patient stratification and to guide targeted therapeutic intervention. Proteomic profiling of extracellular vesicles (EVs) released in biological fluids has recently emerged as a minimally invasive approach to elucidate adult arthritis pathogenic mechanisms and identify new biomarkers. However, EV-prot expression and potential as biomarkers in OJIA have not been explored. This study represents the first detailed longitudinal characterization of the EV-proteome in OJIA patients.
Fourty-five OJIA patients were recruited at disease onset and followed up for 24 months, and protein expression profiling was carried out by liquid chromatography-tandem mass spectrometry in EVs isolated from plasma (PL) and synovial fluid (SF) samples.
We first compared the EV-proteome of SF vs paired PL and identified a panel of EV-prots whose expression was significantly deregulated in SF. Interaction network and GO enrichment analyses performed on deregulated EV-prots through STRING database and ShinyGO webserver revealed enrichment in processes related to cartilage/bone metabolism and inflammation, suggesting their role in OJIA pathogenesis and potential value as early molecular indicators of OJIA development. Comparative analysis of the EV-proteome in PL and SF from OJIA patients vs PL from age/gender-matched control children was then carried out. We detected altered expression of a panel of EV-prots able to differentiate new-onset OJIA patients from control children, potentially representing a disease-associated signature measurable at both the systemic and local levels with diagnostic potential. Deregulated EV-prots were significantly associated with biological processes related to innate immunity, antigen processing and presentation, and cytoskeleton organization. Finally, we ran WGCNA on the SF- and PL-derived EV-prot datasets and identified a few EV-prot modules associated with different clinical parameters stratifying OJIA patients in distinct subgroups.
These data provide novel mechanistic insights into OJIA pathophysiology and an important contribution in the search of new candidate molecular biomarkers for the disease.
Summary Background Little evidence-based information is available to guide the treatment of oligoarticular juvenile idiopathic arthritis. We aimed to investigate whether oral methotrexate increases ...the efficacy of intra-articular corticosteroid therapy. Methods We did this prospective, open-label, randomised trial at ten hospitals in Italy. Using a concealed computer-generated list, children younger than 18 years with oligoarticular-onset disease were randomly assigned (1:1) to intra-articular corticosteroids alone or in combination with oral methotrexate (15 mg/m2 ; maximum 20 mg). Corticosteroids used were triamcinolone hexacetonide (shoulder, elbow, wrist, knee, and tibiotalar joints) or methylprednisolone acetate (ie, subtalar and tarsal joints). We did not mask patients or investigators to treatment assignments. Our primary outcome was the proportion of patients in the intention-to-treat population who had remission of arthritis in all injected joints at 12 months. This trial is registered with European Union Clinical Trials Register, EudraCT number 2008-006741-70. Findings Between July 7, 2009, and March 31, 2013, we screened 226 participants and randomly assigned 102 to intra-articular corticosteroids alone and 105 to intra-articular corticosteroids plus methotrexate. 33 (32%) patients assigned to intra-articular corticosteroids alone and 39 (37%) assigned to intra-articular corticosteroids and methotrexate therapy had remission of arthritis in all injected joints (p=0·48). Adverse events were recorded for 20 (17%) patients who received methotrexate, which led to permanent treatment discontinuation in two patients (one due to increased liver transaminases and one due to gastrointestinal discomfort). No patient had a serious adverse event. Interpretation Concomitant administration of methotrexate did not augment the effectiveness of intra-articular corticosteroid therapy. Future studies are needed to define the optimal therapeutic strategies for oligoarticular juvenile idiopathic arthritis. Funding Italian Agency of Drug Evaluation.
We describe a 2 year old boy with two previously undescribed frameshift mutations in the interferon (IFN)α/β receptor 2 (
IFNAR2
) gene presenting with hemophagocytic lymphohistiocytosis (HLH) ...following measles-mumps-rubella vaccination. Functional analyses show the absence of response to type I IFN in the patient’s cells, as revealed by the lack of phosphorylation of STAT1 and the lack of induction of interferon-stimulated genes upon
ex vivo
stimulation with IFNα. HLH has been reported in patients with inborn errors of type I IFN-mediated immune responses following vaccination with live-attenuated viruses. The relation between HLH and defective type I IFN-mediated responses is unclear. We show that in patient’s natural killer (NK) cells stimulated with IFNα the expected increase in degranulation and inhibition of IFNγ production were affected. These data support a role for NK cell function dysregulation and lack of inhibition of IFNγ production as contributors to the development of HLH in patients with impaired type I IFN signaling.
In encyclopaedic dictionaries published until 1955, the word "tumour" was defined as an "occupational disease suffered by the workers of chemical industries", thus referring to a very specific cause .......
Background Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA) is the most common cause of periodic fever in childhood. Although PFAPA is generally a self-limited ...condition, it can have negative impact on child's and parents’ quality of life and family functioning. Our primary aim was to assess the potential effectiveness of Streptococcus Salivarius K12 (SSK12) in preventing febrile attacks in PFAPA patients. Secondary objectives included evaluating the effectiveness of SSK12 in mitigating the severity of febrile episodes seen as a statistically significant reduction in the episode duration, highest fever temperature reached during fever, in the frequency of each associated symptom, calculated in the six months before and after the start of therapy. Results A total of 117 patients with PFAPA were evaluated using Marshall's criteria, modified by Thomas et al. and according to Eurofever/PRINTO classification criteria, aged 6 months to 9 years, with a median age at the onset of the disease of 2 years, treated with SSK12, since January 2021 to January 2023. Data were collected retrospectively. Before using SS K12, febrile episodes recurred on average every 26.1 ± 11.5 days, with a febrile episode duration of 4.1 ± 1.4 days. The highest fever temperature during the episode was 39.8 ± 0.7 °C. After six months of SS K12, febrile episodes recurred on average every 70 ± 53,1 days ( p value <0.01), the mean lenght of febrile episodes was 3.3 ± 1.6 ( p value <0.01) and the highest fever temperature reached during the febrile episode was 39.1 ± 1.1 °C ( p value <0.01). We also documented a reduction in the frequency of exudative pharyngotonsillitis present in 72 vs. 103 patients ( p value <0.01), oral aphthosis present in 47 vs. 80 patients ( p value <0.01), lateral cervical lymphadenopathy in 45 vs. 83 ( p value <0.01). Erythematous pharyngotonsillitis decreased in frequency but it was not statistically significant. Conclusions The results of our study indicate that the use of SS K12 could be beneficial in decreasing febrile episodes related to PFAPA syndrome and its associated symptoms, potentially improving the quality of life in pediatric patients and decreasing the need for additional pharmacological therapies.
Behçet's disease is a rare multi-systemic inflammatory disease with unknown etiology which involves principally oral and genital mucosa, skin and eyes. Average age at onset of the disease is about ...25-30 years, but it may be diagnosed before the age of 16. It is not very rare in Italy, even though there are limited data concerning epidemiology. Aim of this study is to describe the baseline data of an Italian cohort of patients with as having BD or probable BD.
We described the baseline data of the first national epidemiological study on children coming from 16 Italian Pediatric Rheumatologic Centers diagnosed by the treating physicians as having Behçet's Disease. Data on demographic characteristics, clinical features and therapy were collected. We then compared our findings to those of international pediatric cohort studies and also retrospectively evaluated the ability to diagnose BD using ISG, ICBD and, for the first time, the new PEDBD criteria.
The study included 110 patients (62 M, 48F). Average age at onset was 8.34±4.11 years. The frequencies of signs/symptoms were: recurrent oral aphtosis 94.5%, genital ulcers 33.6%, ocular 43.6%, gastrointestinal 42.7%, musculoskeletal 42.7%, neurological 30.9% and vascular involvement 10%. Thirty-two patients (29.1%) fulfilled ISG, 78 (70.9%) ICBD, 50 (45.5%) PEDBD criteria and 31 (28%) didn't fulfill any of them. The most frequently used treatments were colchicine and corticosteroids followed by immunosuppressants. Four patients received biologic therapy (anti TNF-α and anti-IL-1) to treat severe organ involvement.
Recurrent oral aphtosis was the most frequent clinical manifestation, followed by ocular involvement. Gastrointestinal lesions were more frequent in Italy than in non-European countries as opposed to genital ulcers. Skin, ocular and vascular manifestations had a higher frequency in males and genital ulcers in females. Constitutional symptoms were present in 44.5% and recurrent fever in one third of our population.
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