A clinical perspective on imaging in juvenile idiopathic arthritis.

In recent years, imaging has become increasingly important to confirm diagnosis, monitor disease activity, and predict disease course and outcome in children with juvenile idiopathic arthritis (JIA). Over the past few decades, great efforts have been made to improve the quality of diagnostic imaging and to reach a consensus on which methods and scoring systems to use. However, there are still some critical issues, and the diagnosis, course, and management of JIA are closely related to clinical assessment. This review discusses the main indications for conventional radiography (XR), musculoskeletal ultrasound (US), and magnetic resonance imaging (MRI), while trying to maintain a clinical perspective. The diagnostic-therapeutic timing at which one or the other method should be used, depending on the disease/patient phenotype, will be assessed, considering the main advantages and disadvantages of each imaging modality according to the currently available literature. Some brief clinical case scenarios on the most frequently and severely involved joints in JIA are also presented.

High incidence of multisystem inflammatory syndrome and other autoimmune diseases after SARS-CoV-2 infection compared to COVID-19 vaccination in children and adolescents in south central Europe.

OBJECTIVES: To estimate the incidence and describe the spectrum of inflammatory and autoimmune diseases linked to SARS-CoV-2 infection and COVID-19 vaccination in children from two neighbouring south central European countries. METHODS: We performed a multi-centre prospective cohort study of children under 18 years diagnosed with inflammatory/autoimmune diseases linked to SARS-CoV-2 infection or COVID-19 vaccination, who were admitted to the paediatric tertiary care hospitals in Slovenia and Friuli Venezia Giulia, Italy, from January 1, 2020, to December 31, 2021. Disease incidence was calculated based on laboratory-confirmed cases only. RESULTS: Inflammatory and autoimmune diseases linked to SARS-CoV-2 were diagnosed in 192 children (127 laboratory-confirmed), of whom 112 had multisystem inflammatory syndrome (MIS-C), followed by vasculitis, neurological and cardiac diseases. Calculated risk of MIS-C was 1 in 860 children after SARS-CoV-2 infection and cumulative incidence of MIS-C was 18.3/100,000 of all children. Fifteen children had severe COVID-19. Two patients with MIS-C and a patient with myositis presented after COVID-19 vaccination. All 3 had at presentation also a serologically proven recent SARS-CoV-2 infection. After MIS-C, nine patients were vaccinated against COVID-19 and 25 patients had a SARS-CoV-2 reinfection, without recurrence of MIS-C. CONCLUSIONS: Autoimmune diseases following SARS-CoV-2 infection in children were 8.5 times as common as severe COVID-19. MIS-C was the most common manifestation and its incidence in this predominantly white population was higher than previously reported. MIS-C does not seem to recur after SARS-CoV-2 reinfection or COVID-19 vaccination. Autoimmune diseases were much more common after SARS-CoV-2 infection than after COVID-19 vaccination.

Vaccination coverage in children with rheumatic diseases.

OBJECTIVES: To assess vaccination status in a cohort of children with rheumatic diseases followed at the University Children's Hospital Ljubljana and to evaluate the most common reasons for vaccination dropout. METHODS: Patients with rheumatic diseases who were evaluated at the rheumatology outpatient clinic between January 2015 and January 2017 received a questionnaire about their vaccination status and reasons for potential vaccination dropout. Vaccination coverage for individual vaccines was determined at 5, 10, 18 years and at the time of their last clinic visit. RESULTS: Data were received from 187 out of 424 enrolled patients (44.1%). Majority of included patients had juvenile idiopathic arthritis (n=165), followed by childhood-onset systemic lupus erythematosus (n=6), juvenile dermatomyositis (n=5), mixed connective tissue disease (n=3), chronic recurrent multifocal osteomyelitis, juvenile systemic sclerosis, Takayasu's arteritis (n=2 each), granulomatous polyangiitis and fibromyalgia (n=1 each). Vaccination coverage was complete in 91.9%, 70.3%, 66.7% and 64.7% of patients at 5, 10, 18 years and at their last clinic visit, respectively. Most commonly omitted vaccines were hepatitis B and second dose of measles, mumps and rubella vaccine. Most common additional vaccine was against rotavirus. Most common reason for vaccination dropout was suggestion of the treating rheumatologist. CONCLUSIONS: Thirty-five percent of our patients remain incompletely vaccinated and thus susceptible to vaccine-preventable diseases. Physicians play a crucial role in the decision to vaccinate.

Chronic non-bacterial osteomyelitis: a retrospective international study on clinical manifestations and response to treatment.

OBJECTIVES: Chronic non-bacterial osteomyelitis (CNO) is a rare non-infectious bone inflammatory disorder; when multifocal, it is referred to as Chronic Recurrent Multifocal Osteomyelitis (CRMO). This study evaluates the demographic, clinical and radiological characteristics of a multi-centre cohort of patients with CNO/CRMO. METHODS: Demographic and clinical data of patients with an established diagnosis of CNO/CRMO followed at paediatric rheumatology centres across Europe (Italy, France, Slovenia) and India were retrospectively collected. RESULTS: There were no demographic differences across countries, but time to diagnosis was significantly longer in India (p=0.041). Pain was almost invariably present at disease onset; functional impairment was more frequent among Italian and Slovenian patients (p=0.001). The number of sites of bone involvement was similar between genders and countries, with long bone metaphises being the most common site. Raised acute phase reactants, detected in >50% of patients, were not associated with clinical manifestations or response to treatment. Comorbidities, evinced in 37% of patients, were equally distributed between genders and nationalities. Imaging approach was similar across countries, without any association between radiological findings and clinical manifestations. NSAIDs were almost invariably used as first-line treatment, but response rate was significantly lower in Italy (p=0.02). Methotrexate was used in 28% of case, with an overall rate of response of 82%. Health conditions and rate of permanent deformities were similar across different countries. CONCLUSIONS: The differences in clinical presentation, radiological features and response to treatment described in this multinational cohort of CNO/CRMO might provide novel insights into this still elusive disease.

Antiphospholipid syndrome in children.

Antiphospholipid syndrome (APS) in children is a rare disease associated with significant morbidity and mortality. In comparison with APS in adults, pediatric APS has a more severe presentation with frequent recurrences of thrombotic events and a higher probability of life-threatening catastrophic APS. Nonthrombotic manifestations are also more common in the pediatric age group and can precede thrombosis. New classification criteria have been introduced recently and have not yet been assessed in pediatric patients with APS. In addition to anticoagulation drugs, other novel therapies have emerged including the use of B cell and complement inhibitors, especially in catastrophic APS. The purpose of this review is to provide a broad overview of aPL-related clinical manifestations in pediatric patients based on the analysis of published cohorts and data from the international pediatric APS registry. We also aim to illustrate APS in infants caused by transplacentally transferred maternal aPL, which is very rarely associated with acute thrombotic events in the perinatal period and more frequently with long-term neurodevelopmental abnormalities.

Long-term follow-up of 109 children with juvenile idiopathic oligoarthritis after first intra-articular corticosteroid injection.

BACKGROUND: To evaluate long-term outcomes and prognostic factors in patients with juvenile idiopathic arthritis (JIA), presenting as oligoarthritis, who received IAC as the first treatment for their disease. METHODS: We conducted retrospective study at the University Children's Hospital Ljubljana, Slovenia, from January 2015 to May 2023 in children with JIA, clinically presenting as oligoarthritis receiving intra-articular corticosteroid injection (IAC) as the initial treatment. Patient and treatment data were collected, and the outcomes were categorized into three groups based on the later need for therapy: no therapy needed, only additional IAC needed and systemic therapy needed. The last group was further divided based on the requirement of bDMARD. Log-rank (Mantel-Cox) survival analyses compared different outcome groups. RESULTS: We included 109 patients with JIA, presenting as oligoarthritis (63% female), who were first treated with IAC. The mean age at IAC was 8.0 years, with a 4.3-year follow-up. Notably, 38.5% of patients did not require additional therapy post-IAC, whereas 15.5% required only additional IAC. Systemic therapy, mainly methotrexate (MTX), was necessary for 45.9% of patients, initiated in average 7.8 months post-IAC. Biologic therapy was initiated in 22% in average 2.2 years post-IAC. Number of injected joints correlated with the need for biologics. At the last follow-up, 88.9% had inactive disease. ANA positivity (P = 0.049, chi square 3.89) and HLA B27 antigen presence (P = 0.050, chi square 3.85) were associated with the need for systemic therapy. A subgroup of children older than 8 years, ANA and HLA B27 negative required significantly less systemic (25.8%) and biologic therapy (9.6%) compared to other patients (p = 0.050, chi square 3.77). CONCLUSION: Almost 40% of children with oligoarticular JIA requiring IAC did not progress to chronic disease. Younger age, ANA positivity, and HLA B27 presence were predictive factors for systemic therapy, while the number of injected joints predicted the future need for biologic therapy.

Serological response after COVID-19 infection compared to vaccination against COVID-19 in children with autoimmune rheumatic diseases.

BACKGROUND: Paediatric patients with autoimmune rheumatic diseases (pARD) have a dysregulated immune system, so infections present a major threat to them. To prevent severe COVID-19 infections we aimed to vaccinate them as soon as possible. Studies have shown that the BNT162b2 vaccine is safe, effective, and immunogenic, however, in a short observation period, only. METHODS: The main objective was to compare the serological response between three groups of pARD: after SARS-CoV-2 infection, after vaccination against COVID-19 with two doses of the BNT162b2 vaccine, and after experiencing both events. Data on demographics, diagnosis, therapy, and serology (anti-SARS-CoV-2 IgG/IgA) were collected from March 2020 to April 2022. For statistical analysis ANOVA, Mann-Whitney U test, Chi-square test and Fisher's exact test were applied. To compare adverse events (AE) after vaccination we included a control group of healthy adolescents. RESULTS: We collected data from 115 pARD; from 92 after infection and 47 after vaccination. Twenty-four were included in both groups. Serological data were available for 47 pARD after infection, 25 after vaccination, and 21 after both events. Serological response was better after vaccination and after both events compared to after infection only. No effect of medication on the antibody levels was noted. The safety profile of the vaccine was good. Systemic AE after the first dose of the vaccine were more common in healthy adolescents compared to pARD. In the observation period of 41.3 weeks, 60% of vaccinated pARD did not experience a symptomatic COVID-19 infection. CONCLUSIONS: IgG and IgA anti-SARS-CoV-2 levels were higher after vaccination and after both events compared to after infection only. Six months after vaccination we observed an increase in antibody levels, suggesting that pARD had been exposed to SARS-CoV-2 but remained asymptomatic. TRIAL REGISTRATION: The study was approved by the Medical Ethics Committee of the Republic of Slovenia (document number: 0120-485/2021/6).

Disease relapse rate in children with autoimmune rheumatic diseases after COVID-19 infection and vaccination.

BACKGROUND: Paediatric patients with autoimmune rheumatic diseases (pARD) are often immunocompromised because of the disease and/or the therapy they receive. At the beginning of COVID-19 pandemic there was a great concern about the possibility of severe SARS-CoV-2 infection in these patients. The best method of protection is vaccination, so as soon as vaccine was licenced, we aimed to vaccinate them. Data on disease relapse rate after COVID-19 infection and vaccination are scarce, but they play important role in everyday clinical decisions. METHODS: The aim of this study was to determine the relapse rate of autoimmune rheumatic disease (ARD) after COVID-19 infection and vaccination. Data on demographic, diagnosis, disease activity, therapy, clinical presentation of the infection and serology were collected from pARD who had COVID-19 and from pARD who were vaccinated against COVID-19, from March 2020 to April 2022. All vaccinated patients received two doses of the BNT162b2 BioNTech vaccine, on average, 3.7 (S.D.=1.4) weeks apart. Activity of the ARD was followed prospectively. Relapse was defined as a worsening of the ARD in a time frame of 8 weeks after infection or vaccination. For statistical analysis, Fisher's exact test and Mann-Whitney U test were used. RESULTS: We collected data from 115 pARD, which we divided into two groups. We included 92 pARD after infection and 47 after vaccination, with 24 in both groups (they were infected before/after vaccination). In 92 pARD we registered 103 SARS-CoV-2 infections. Infection was asymptomatic in 14%, mild in 67% and moderate in 18%, 1% required hospitalization; 10% had a relapse of ARD after infection and 6% after vaccination. There was a trend towards higher disease relapse rate after infection compared to vaccination, but the difference was not statistically significant (p = 0.76). No statistically significant difference was detected in the relapse rate depending on the clinical presentation of the infection (p = 0.25) or the severity of the clinical presentation of COVID-19 between vaccinated and unvaccinated pARD (p = 0.31). CONCLUSIONS: There is a trend towards a higher relapse rate in pARD after infection compared to vaccination and connection between the severity of COVID-19 and vaccination status is plausible. Our results were, however, not statistically significant.

Comprehensive Care and Education Can Improve Nutritional and Growth Outcomes in Children with Persistent Cow's Milk, Egg, or Peanut Allergies: A Five-Year Follow-Up Study of Nutritional Status.

BACKGROUND: Data suggest that food allergies greatly impact a child's health and growth due to inadequate nutrient intake. Our study aimed to establish the long-term outcome of children with food allergies compared to a control group. METHODS: This study was a retrospective cohort study with longitudinal follow-up with a mean period of 4.85 years from the diagnosis to the last study visit. The patients' nutritional intake was assessed using a three-day food diary and analysed by a dietitian. Patients (61 boys and 33 girls, mean age 6.9 years) had a single food allergy including 21 patients with cow's milk, 34 with egg, and 39 with peanut allergies. The control group included 36 children (19 boys and 17 girls, mean age 8.03 years). Blood analysis was performed on all participants. RESULTS: Data from our study showed that patients with cow's milk, egg or peanut allergies had normal growth and achieved catch-up growth from the diagnosis until the last study visit. In the cow's milk allergy group, the allergy was shown to affect calcium intake (p < 0.05), while egg and peanut allergies did not impact the dietary intake of nutrients. None of the investigated food allergies affected blood results (p < 0.05). CONCLUSIONS: In the present study, we showed that single food allergies do not compromise growth in children if they are provided with appropriate support and that the affected children reach catch-up growth from the diagnosis.

Relationship Between Polymorphisms in Methotrexate Pathway Genes and Outcome of Methotrexate Treatment in a Cohort of 119 Patients with Juvenile Idiopathic Arthritis.

OBJECTIVE: To identify clinical and pharmacogenetic determinants of efficacy and toxicity of methotrexate (MTX) in juvenile idiopathic arthritis (JIA) over time. METHODS: A cohort of 119 consecutive patients with JIA treated with MTX was reviewed. The Juvenile Arthritis Disease Activity Score including 71 joints was used to measure disease activity. Nonresponders were patients who did not reach a minimum of 30% improvement after 6 months of treatment or were switched to biologic drugs in the first 6 months because of inefficacy. All adverse events (AE) were noted. Genotyping of single-nucleotide polymorphisms (SNP) in the genes coding for MTX transporters, folate pathway, and adenosine pathway was performed using real-time PCR methods. Univariate and multivariable penalized logistic and Cox regression were used to analyze data. RESULTS: Thirty patients (25.8%) were defined as nonresponders and 55 (47.2%) were switched to biologics during the followup. Sixty-five patients (54.5%) reported AE in a total of 405 patient-years, and 10 patients (8.4%) discontinued MTX because of AE. AMPD1 rs17602729 and MTHFD1 rs2236225 were associated with gastrointestinal AE while the latter together with MTRR rs1801394 also demonstrated associations with developing hepatoxicity. MTHFR rs1801131, ABCG2 rs2231137, wild-type of MTR rs1805087, and wild-type of ABCC2 rs2273697 were identified as potential markers for discontinuing MTX treatment because of AE. MTHFR rs1801133, MTRR rs1801394, and ABCC2 rs2273697 were associated with switching to biologics. CONCLUSION: SNP in different MTX metabolic pathways influence treatment with MTX. Genetic variability is a better marker for toxicity than efficacy.