Nowadays, digital health technologies, including mobile apps, wearable technologies, social media, websites, electronic medical records, and artificial intelligence, are impacting disease management and outcomes. We aimed to analyse the characteristics and use of digital health tools in juvenile idiopathic arthritis (JIA).

We conducted a systematic review (SR) to identify articles examining the characteristics, use, and outcomes (feasibility, usability, and effectiveness) of digital health tools in JIA patients. A sensitive search strategy was performed in Medline, Embase, and Cochrane databases until December 2022 (later updated to March 2024). Two reviewers independently selected the studies and collected the data, including study quality. A descriptive analysis was performed.

A total of 21 studies were included, one SR, six randomised controlled trials, four observational studies, four validation studies, one discovery and verification study, and five qualitative studies. Study quality was generally moderate. Most studies focused on patients with JIA (especially young people), but also on parents and health care professionals. Different digital health technologies were investigated, like websites, mobile apps, wearables, and telemedicine. The main objectives of the tools were self-management, symptom and quality of life monitoring, physical activity tracking, disease knowledge improvement, and medication monitoring. Different themes and contents were usually included in the same digital health tool, such as psychological health, lifestyle, intimacy, or shared decision-making. Tool development and validation processes were poorly or not at all described, and data regarding regulatory compliance, security, or privacy were scarce.

There is significant variability in the type, characteristics, objectives, and contents of digital health tools for JIA. They still show limitations and gaps, thus highlighting the need for better critical assessment and reporting.

Juvenile idiopathic arthritis (JIA) is a rheumatic disorder that causes chronic joint inflammation beginning before the age of 16 years. Pharmacological treatment necessary to prevent joint destruction and functional impairment includes non-steroidal anti-inflammatory drugs (NSAIDs), intra-articular corticosteroids, conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs) like methotrexate (MTX), and biologic DMARDs (bDMARDs) such as tumor necrosis factor inhibitors (TNFi), abatacept, anakinra, and tocilizumab. More recently, targeted synthetic DMARDs (tsDMARDs) like tofacitinib, baricitinib, and upadacitinib have been approved for the treatment of JIA.

To assess the benefits and harms of TNFi in children with JIA.

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (via Ovid), Embase (via Ovid), and ClinicalTrials.gov and the WHO ICTRP from inception to 28 February 2024, with no language restrictions.

We included randomized controlled trials (RCTs), quasi-RCTs, and data from the randomized part of withdrawal trials conducted in individuals with JIA where TNFi were compared to placebo, MTX, NSAIDs, other bDMARDs, tsDMARDs, or other TNFi. Our major outcomes were treatment response, pain, function, participant global assessment of well-being (disease activity), remission, withdrawals due to adverse events, and serious adverse events.

We used standard Cochrane methods. At least two review authors performed study selection, data extraction, and risk of bias and GRADE assessment. The primary comparison was TNFi versus placebo. The primary time point was up to 16 weeks and up to the end of the trials for efficacy and safety outcomes, respectively.

We included nine studies with 678 participants (80% females) with JIA. The mean age of participants ranged from 8 to 15 years, and the mean duration of symptoms ranged from 0.8 years to 6.7 years. Seven studies compared TNFi to placebo (570 participants), and two studies compared TNFi combined with MTX to MTX alone (108 participants). We identified no studies investigating the other predefined comparisons. Only two studies had a low risk of bias in all domains, while five studies had a high risk of bias in at least one domain, predominantly other bias. Two studies were at unclear risk of selection bias, and two studies were at unclear risk of detection bias. TNFi versus placebo Benefits at up to 16 weeks Low-certainty evidence (downgraded for risk of bias and imprecision) suggests that treatment with TNFi may increase the likelihood of achieving a treatment response, defined as pedACR70 (34% compared to 14% with placebo) (risk ratio [RR] 2.47, 95% confidence interval [CI] 1.48 to 4.14; 4 studies, 245 participants). The evidence is very uncertain (downgraded for indirectness and imprecision) for the effect of TNFi on pain, with mean pain scores (visual analogue scale [VAS] 0 to 100, 0 no pain, minimal clinically important difference [MCID] = 15 mm) lower with TNFi (11 mm) compared to placebo (33 mm) (mean difference [MD] 22 mm, 95% CI 50 mm lower to 5.7 mm higher; 2 studies, 72 participants). Similarly, the effect of TNFi on function (Childhood Health Assessment Questionnaire [CHAQ], 0 to 3, 0 normal function) and quality of life (global assessment of well-being, VAS 0 to 100 mm, 0 no disease activity) is very uncertain. Mean function was 0.84 with TNFi and 1 with placebo (MD 0.16 lower, 95% CI 0.39 lower to 0.06 higher; 3 studies, 194 participants; very low-certainty evidence, downgraded for risk of bias and imprecision). The mean participant global assessment of well-being was 23 mm with TNFi and 34 mm with placebo (MD 11 mm lower, 95% CI 23 mm lower to 1 mm higher; 3 studies, 194 participants; very low-certainty evidence, downgraded for indirectness, imprecision, and risk of bias). No study reported data on remission. Harms at any time We are uncertain about the effect of TNFi on withdrawals due to adverse events (3%) compared to placebo (1%) (RR 3.41, 95% CI 0.73 to 15.9; 6 studies, 448 participants). We are also uncertain about the effect of TNFi on serious adverse events (7%) compared to placebo (6%) (RR 1.09, 95% CI 0.53 to 2.22; 6 studies, 448 participants). The certainty of evidence was very low, downgraded for risk of bias and imprecision. TNFi plus MTX versus MTX alone Benefits at 17 to 26 weeks We are uncertain about the effect of TNFi plus MTX on treatment response. Seventy per cent of participants receiving MTX and 90% receiving TNFi plus MTX achieved treatment response (RR 1.29, 95% CI 0.93 to 1.77; 1 study, 40 participants). We are also uncertain about the effect of TNFi plus MTX on remission. Five per cent of participants on MTX monotherapy and 40% on combination therapy were in remission (RR 8.00, 95% CI 1.10 to 58.19; 1 study, 40 participants). No study reported pain, function, or participant global assessment of well-being. Harms at any time We are uncertain about the effect of TNFi plus MTX on withdrawals due to adverse events and serious adverse events. Very low-certainty evidence from two studies shows that 2/53 participants (4%) receiving MTX alone and 3/55 (5%) receiving TNFi plus MTX withdrew due to adverse events (RR 1.31, 95% CI 0.18 to 9.82; 108 participants), and 5/53 (9%) receiving MTX alone and 0/55 receiving TNFi plus MTX reported serious adverse events (RR 0.16, 95% CI 0.02 to 1.32). Due to risk of bias and imprecision, the certainty of evidence was very low across all major outcomes for this comparison.

In JIA, TNFi may result in a higher proportion of individuals achieving clinical improvement compared to placebo, but we are uncertain about the effect of TNFi on pain, function, and quality of life. We are also uncertain about the effect of TNFi combined with MTX versus MTX alone on clinical improvement and remission. Evidence for the safety of TNFi compared to placebo or MTX is very uncertain. There are no RCTs comparing TNFi to other treatments. More high-quality studies are warranted to assess the benefits and harms of TNFi in JIA.

The onset of the coronavirus disease 2019 (COVID-19) necessitated a rapid transition to virtual care for chronic pain treatment.

This study examined experiences of patients and caregivers who received virtual multidisciplinary pain treatment (MDT) for pediatric chronic pain between March 2020 and August 2021.

A mixed methods design was implemented using qualitative interviews and quantitative satisfaction surveys. Satisfaction surveys were administered to a convenience sample of patients (aged 8 to 18; N = 20) and their caregivers (N = 20) who received MDT through an outpatient hospital pediatric chronic pain program. Interviews were conducted with a subset of these patients and their caregivers (n = 6).

Analysis of interviews revealed four themes: 1) benefits of virtual care; 2) challenges of virtual care; 3) recommendations and evaluation of virtual care; and 4) patient preferences. Analysis of the satisfaction survey data revealed that while patients and caregivers were satisfied with many aspects of virtual care, 65% (n = 13) of patients reported a preference for in-person appointments, with caregivers showing equal preference for in-person and virtual appointments, though this was a non-significant difference (p = .37). Overall, both patients and caregivers stated a stronger preference for in-person physiotherapy sessions but were willing to have psychology sessions provided virtually. Finally, the most reported preference was for a hybrid model of care incorporating at least some in-person contact with providers.

This study provides a rich exploration of virtual care for multidisciplinary pediatric chronic pain treatment. The current results may inform the future development of guidelines for virtual care delivery with pediatric chronic pain populations.

Background: Pulmonary involvement in systemic juvenile idiopathic arthritis (SJIA) is a rare but dangerous complication. The main risk factors are already known, such as macrophage activation syndrome, a refractory course of systemic juvenile arthritis, infusion reaction to interleukin 1 and/or interleukin 6 blockers, trisomy 21, and eosinophilia. However, information about respiratory system involvement (RSI) at the onset of SJIA is scarce. Our study aimed to evaluate the specific features of children with SJIA with RSI and their outcomes. Methods: In a single-center retrospective cohort study, we compared the information from the medical records of 200 children with SJIA according to ILAR criteria or SJIA-like disease (probable/possible SJIA) with and without signs of RSI (dyspnea, shortness of breath, pleurisy, acute respiratory distress syndrome, and interstitial lung disease (ILD)) at the disease onset and evaluated their outcomes (remission, development of chronic ILD, clubbing, and pulmonary arterial hypertension). Results: A quarter (25%) of the SJIA patients had signs of the RSI at onset and they more often had rash; hepato- and splenomegaly; heart (pericarditis, myocarditis), central nervous system, and kidney involvement; hemorrhagic syndrome; macrophage activation syndrome (MAS, 44.4% vs. 9.0%, p = 0.0000001); and, rarely, arthritis with fewer active joints, compared to patients without RSI. Five patients (10% from the group having RSI at the onset of SJIA and 2.5% from the whole SJIA cohort) developed fibrosing ILD. All of them had a severe relapsed/chronic course of MAS; 80% of them had a tocilizumab infusion reaction and further switched to canakinumab. Unfortunately, one patient with Down's syndrome had gone. Conclusion: Patients with any signs of RSI at the onset of the SJIA are required to be closely monitored due to the high risk of the following fibrosing ILD development. They required prompt control of MAS, monitoring eosinophilia, and routine checks of night oxygen saturation for the prevention/early detection of chronic ILD.

Lung damage in systemic juvenile arthritis (sJIA) is one of the contemporary topics in pediatric rheumatology. Several previous studies showed the severe course and fatal outcomes in some patients. The information about interstitial lung disease (ILD) in the sJIA is scarce and limited to a total of 100 cases.

To describe the features of sJIA patients with ILD in detail.

In the present retrospective cohort study, information about 5 patients less than 18-years-old with sJIA and ILD were included. The diagnosis of sJIA was made according to the current 2004 and new provisional International League of Associations for Rheumatology criteria 2019. ILD was diagnosed with chest computed tomography with the exclusion of other possible reasons for concurrent lung involvement. Macrophage activation syndrome (MAS) was diagnosed with HLH-2004 and 2016 EULAR/ACR/PRINTO Classification Criteria and hScores were calculated during the lung involvement.

The onset age of sJIA ranged from 1 year to 10 years. The time interval before ILD ranged from 1 mo to 3 years. The disease course was characterized by the prevalence of the systemic features above articular involvement, intensive rash (100%), persistent and very active MAS (hScore range: 194-220) with transaminitis (100%), and respiratory symptoms (100%). Only 3 patients (60%) developed a clubbing phenomenon. All patients (100%) had pleural effusion and 4 patients (80%) had pericardial effusion at the disease onset. Two patients (40%) developed pulmonary arterial hypertension. Infusion-related reactions to tocilizumab were observed in 3 (60%) of the patients. One patient with trisomy 21 had a fatal disease course. Half of the remaining patients had sJIA remission and 2 patients had improvement. Lung disease improved in 3 patients (75%), but 1 of them had initial deterioration of lung involvement. One patient who has not achieved the sJIA remission had the progressed course of ILD. No cases of hyper-eosinophilia were noted. Four patients (80%) received canakinumab and one (20%) tocilizumab at the last follow-up visit.

ILD is a severe life-threatening complication of sJIA that may affect children of different ages with different time intervals since the disease onset. Extensive rash, serositis (especially pleuritis), full-blown MAS with transaminitis, lymphopenia, trisomy 21, eosinophilia, and biologic infusion reaction are the main predictors of ILD. The following studies are needed to find the predictors, pathogenesis, and treatment options, for preventing and treating the ILD in sJIA patients.

A vast body of evidence provides support to a central role of exaggerated production of interferon-γ (IFN-γ) in causing hypercytokinemia and signs and symptoms of hemophagocytic lymphohistiocytosis (HLH). In this chapter, we will describe briefly the roles of IFN-γ in innate and adaptive immunity and in host defense, summarize results from animal models of primary HLH and secondary HLH with particular emphasis on targeted therapeutic approaches, review data on biomarkers associated with activation of the IFN-γ pathway, and discuss initial efficacy and safety results of IFN-γ neutralization in humans.

Chronic pain is a major health and socioeconomic burden, which is prevalent in children and adolescents. Among the most widely used interventions in children and adolescents are physical activity (including exercises) and education about physical activity.

To evaluate the effectiveness of physical activity, education about physical activity, or both, compared with usual care (including waiting-list, and minimal interventions, such as advice, relaxation classes, or social group meetings) or active medical care in children and adolescents with chronic musculoskeletal pain.

We searched CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, PEDro, and LILACS from the date of their inception to October 2022. We also searched the reference lists of eligible papers, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform.

We included randomised controlled trials (RCTs) that compared physical activity or education about physical activity, or both, with usual care (including waiting-list and minimal interventions) or active medical care, in children and adolescents with chronic musculoskeletal pain.

Two review authors independently determined the eligibility of the included studies. Our primary outcomes were pain intensity, disability, and adverse events. Our secondary outcomes were depression, anxiety, fear avoidance, quality of life, physical activity level, and caregiver distress. We extracted data at postintervention assessment, and long-term follow-up. Two review authors independently assessed risk of bias for each study, using the RoB 1. We assessed the overall certainty of the evidence using the GRADE approach. We reported continuous outcomes as mean differences, and determined clinically important differences from the literature, or 10% of the scale.

We included four studies (243 participants with juvenile idiopathic arthritis). We judged all included studies to be at unclear risk of selection bias, performance bias, and detection bias, and at high risk of attrition bias. We downgraded the certainty of the evidence for each outcome to very low due to serious or very serious study limitations, inconsistency, and imprecision. Physical activity compared with usual care Physical activity may slightly reduce pain intensity (0 to 100 scale; 0 = no pain) compared with usual care at postintervention (standardised mean difference (SMD) -0.45, 95% confidence interval (CI) -0.82 to -0.08; 2 studies, 118 participants; recalculated as a mean difference (MD) -12.19, 95% CI -21.99 to -2.38; I² = 0%; very low-certainty evidence). Physical activity may slightly improve disability (0 to 3 scale; 0 = no disability) compared with usual care at postintervention assessment (MD -0.37, 95% CI -0.56 to -0.19; I² = 0%; 3 studies, 170 participants; very low-certainty evidence). We found no clear evidence of a difference in quality of life (QoL; 0 to 100 scale; lower scores = better QoL) between physical activity and usual care at postintervention assessment (SMD -0.46, 95% CI -1.27 to 0.35; 4 studies, 201 participants; very low-certainty evidence; recalculated as MD -6.30, 95% CI -18.23 to 5.64; I² = 91%). None of the included studies measured adverse events, depression, or anxiety for this comparison. Physical activity compared with active medical care We found no studies that could be analysed in this comparison. Education about physical activity compared with usual care or active medical care We found no studies that could be analysed in this comparison. Physical activity and education about physical activity compared with usual care or active medical care We found no studies that could be analysed in this comparison.

We are unable to confidently state whether interventions based on physical activity and education about physical activity are more effective than usual care for children and adolescents with chronic musculoskeletal pain. We found very low-certainty evidence that physical activity may reduce pain intensity and improve disability postintervention compared with usual care, for children and adolescents with juvenile idiopathic arthritis. We did not find any studies reporting educational interventions; it remains unknown how these interventions influence the outcomes in children and adolescents with chronic musculoskeletal pain. Treatment decisions should consider the current best evidence, the professional's experience, and the young person's preferences. Further randomised controlled trials in other common chronic musculoskeletal pain conditions, with high methodological quality, large sample size, and long-term follow-up are urgently needed.

Immunocompromised children are at increased risk of severe illness from vaccine-preventable infections. However, inadequate vaccine coverage remains a concern. This scoping review sought to determine the current state of knowledge regarding vaccine coverage of immunocompromised children. Bibliographic databases were searched for primary research from any year. Data were analyzed quantitatively and narratively. Ninety-seven studies met inclusion criteria. The most commonly studied vaccines were pneumococcal (n = 46), influenza (n = 44), diphtheria/tetanus/pertussis/poliomyelitis/Haemophilus influenzae type B/hepatitis B-containing (n = 36), and measles- and/or mumps- and/or rubella-containing (n = 29). Immunocompromising conditions studied included cancer/stem cell transplants (n = 24), solid organ transplants (n = 23), sickle cell disease (n = 21), immunosuppressive therapy (n = 14), human immunodeficiency virus (n = 12), splenectomy (n = 4), and primary immunodeficiency (n = 2). As more children are treated with immunosuppressive therapies, it is critical to identify whether they are being appropriately vaccinated for age and condition. We identified gaps in the current state of knowledge for specific vaccine types in specific immunocompromised populations.

With the introduction of biological disease-modifying antirheumatic drugs (bDMARDs), the treatment of pediatric patients with autoimmune/inflammatory rheumatic diseases (pedAIIRD) has advanced from the "Stone Age" to modern times, resulting in much better clinical outcomes. However, everything comes with a price, and use of new bDMARDs has resulted in an increased risk of infections. Therefore, preventing infections in pedAIIRD patients is one of the top priorities. The most effective preventive measure against infection is vaccination. The first study on humoral immunity after vaccination in pediatric rheumatology was published in 1974 and on safety in 1993. For many years, data about safety and immunogenicity in pedAIIRD patients were available only for non-live vaccines and the first studies on live-attenuated vaccines in pedAIIRD patients treated with immunosuppressive therapy were available only after 2007. Even today the data are limited, especially for children treated with bDMARDs. Vaccinations with non-live vaccines are nowadays recommended, although their long-term immunogenicity and efficacy in pedAIIRD patients are still under investigation. Vaccinations with live-attenuated vaccines are not universally recommended in immunosuppressed patients. However, measles-mumps-rubella booster and varicella zoster virus vaccination can be considered under specific conditions. Additional research is needed to provide more evidence on safety and immunogenicity, especially regarding live-attenuated vaccines in immunosuppressed patients with pedAIIRD. Due to the limited number of these patients, well-designed, prospective, international studies are needed. Further challenges were presented by the COVID-19 pandemic. This mini review article reviews past and present data and discusses the future of vaccinology in pediatric rheumatology.

Several biologic drugs are available for treatment of immune-mediated diseases, and the number of children treated with biologics is increasing. This review summarises current knowledge about the safety and immunogenicity of vaccines in children treated with biologic therapy.

A recent retrospective, multicentre study reported that the booster dose of live-attenuated vaccine (MMR/V) was safe for patients with rheumatic diseases treated with biologic therapy. Recent publications revealed that immunogenicity of vaccines in children treated with biologics was lower than in the healthy population, especially on long-term follow-up. Children treated with biologic therapy are at greater danger of infections, compared to the healthy population. Therefore, they should be vaccinated according to national guidelines. Regardless of the therapy, non-live vaccines are recommended. However, it is common practice to advise postponing vaccination with live-attenuated vaccines in children while they are on immunosuppressive therapy. Newly published data suggest that booster dose MMR/V is safe for children treated with biologic therapy.

Assessing a patient's perspective on their treatment is part of an increasingly integrated approach to pharmacovigilance and treatment optimization. New tools and methods developed in partnership with patients can capture and quantify cognitive and behavioral aspects of the treatment experience. These treatment insights have the potential to shape the drug development process, as well as supplement patient-reported outcome data in a way that is meaningful to the patient. We highlight examples of tools developed to assess the impact of treatment on the aspects of disease that are of utmost concern to the patient in their daily life.

The primary immunodeficiency diseases (PIDs) include many genetic disorders that affect different components of the innate and adaptive responses. The number of distinct genetic PIDs has increased exponentially with improved methods of detection and advanced laboratory methodology. Patients with PIDs have an increased susceptibility to infectious diseases and non-infectious complications including allergies, malignancies and autoimmune diseases (ADs), the latter being the first manifestation of PIDs in several cases. There are two types of PIDS. Monogenic immunodeficiencies due to mutations in genes involved in immunological tolerance that increase the predisposition to develop autoimmunity including polyautoimmunity, and polygenic immunodeficiencies characterized by a heterogeneous clinical presentation that can be explained by a complex pathophysiology and which may have a multifactorial etiology. The high prevalence of ADs in PIDs demonstrates the intricate relationships between the mechanisms of these two conditions. Defects in central and peripheral tolerance, including mutations in AIRE and T regulatory cells respectively, are thought to be crucial in the development of ADs in these patients. In fact, pathology that leads to PID often also impacts the Treg/Th17 balance that may ease the appearance of a proinflammatory environment, increasing the odds for the development of autoimmunity. Furthermore, the influence of chronic and recurrent infections through molecular mimicry, bystander activation and super antigens activation are supposed to be pivotal for the development of autoimmunity. These multiple mechanisms are associated with diverse clinical subphenotypes that hinders an accurate diagnosis in clinical settings, and in some cases, may delay the selection of suitable pharmacological therapies. Herein, a comprehensively appraisal of the common mechanisms among these conditions, together with clinical pearls for treatment and diagnosis is presented.