Outcomes after anti-tumour necrosis factor originator to biosimilar switching in children and young people with juvenile idiopathic arthritis in the UK: a national cohort study.

BACKGROUND: For cost-saving purposes, children and young people with juvenile idiopathic arthritis (JIA) are being switched (for non-medical reasons) from biological originators to biosimilars. Here, we aimed to investigate those who switched from an anti-tumour necrosis factor (TNF) originator to a biosimilar, regarding drug survival and disease activity, compared with a matched cohort who continued the originator. METHODS: This analysis included all patients in the UK JIA Biologics Register switching directly from an anti-TNF originator to a biosimilar of the same product. All patients were matched (age, sex, disease duration, calendar year of when patients started originator therapy, line of therapy, and International League of Associations for Rheumatology [ILAR] category) to patients continuing the originator. For those matched successfully, a Cox proportional hazard model assessed whether drug persistence differed between those who switched compared with those who continued the originator. Overall change in the 71-joint juvenile arthritis disease activity score and the proportion of patients with a clinically important worsening score (by ≥1·7 units) after 6 months was compared between cohorts. This analysis was designed to address a priority research area set by our patient partners. FINDINGS: There were 224 children and young people with non-systemic JIA (139 [62%] were female, and 85 [38%] were male) identified as switching from a biological originator to a biosimilar of the same product from Jan 1, 2017, to July 7, 2023. 143 (64%) patients were originally on adalimumab, 56 (25%) on etanercept, and 25 (11%) on infliximab. Of these, 164 patients were matched successfully to those continuing the originator. There was no evidence that patients switching were more likely to stop treatment compared with those continuing the originator, with a hazard ratio of 1·46 (95% CI 0·93-2·30). Of the 51 patients in the biosimilar group who stopped treatment, 18 (35%) switched back to the originator (14 in the first year), 28 (55%) started a different biological drug, and five (10%) discontinued all treatment by the last follow-up. Of the 87 matched patients with available disease activity, there was no evidence that JADAS-71 worsened more after 6 months, with an odds ratio of 0·71 (95% CI 0·34-1·51; p=0·38). INTERPRETATION: In this matched comparative effectiveness analysis, children and young people with JIA switched from originators to biosimilars. Disease activity was similar between patients switching compared with those continuing the originator. Three quarters of patients were still receiving their biosimilar after 1 year, with switching back to originator uncommon, at only 9% after 1 year, suggesting good tolerability of non-medical switching in this patient population. This information is reassuring to clinicians and patients regarding the effect of non-medical biological switching. FUNDING: British Society for Rheumatology, Versus Arthritis, and National Institutes for Health Research Manchester Biomedical Research Centre.

Telemedicine in pediatric rheumatology: this is the time for the community to embrace a new way of clinical practice.

BACKGROUND: The use of telemedicine in pediatric rheumatology has been historically low. The current COVID 19 global pandemic has forced a paradigm shift with many centers rapidly adopting virtual visits to conduct care resulting in rapid expansion of use of telemedicine amongst practices. BODY: This commentary discusses practical tips for physicians including guidance around administrative and governance issues, preparation for telemedicine, involving the multidisciplinary care team, and teaching considerations. We also outline a standard proforma and smart phrases for the electronic health record. A proposed variation of the validated pediatric gait arms legs spine examination (pGALS) called the video pGALS (VpGALS) as a means of conducting virtual pediatric rheumatology physical examination is presented. CONCLUSION: This commentary provides a starting framework for telemedicine use in pediatric rheumatology and further work on validation and acceptability is needed.

Different corticosteroid induction regimens in children and young people with juvenile idiopathic arthritis: the SIRJIA mixed-methods feasibility study.

BACKGROUND: In the UK, juvenile idiopathic arthritis is the most common inflammatory disorder in childhood, affecting 10 : 100,000 children and young people aged < 16 years each year, with a population prevalence of around 1 : 1000. Corticosteroids are commonly used to treat juvenile idiopathic arthritis; however, there is currently a lack of consensus as to which corticosteroid induction regimen should be used with various disease subtypes and severities of juvenile idiopathic arthritis. OBJECTIVE: The main study objective was to determine the feasibility of conducting a randomised controlled trial to compare the different corticosteroid induction regimens in children and young people with juvenile idiopathic arthritis. DESIGN: This was a mixed-methods study. Work packages included a literature review; qualitative interviews with children and young people with juvenile idiopathic arthritis and their families; a questionnaire survey and screening log to establish current UK practice; a consensus meeting with health-care professionals, children and young people with juvenile idiopathic arthritis, and their families to establish the primary outcome; a feasibility study to pilot data capture and to collect data for future sample size calculations; and a final consensus meeting to establish the final protocol. SETTING: The setting was rheumatology clinics across the UK. PARTICIPANTS: Children, young people and their families who attended clinics and health-care professionals took part in this mixed-methods study. INTERVENTIONS: This study observed methods of prescribing corticosteroids across the UK. MAIN OUTCOME MEASURES: The main study outcomes were the acceptability of a future trial for children, young people, their families and health-care professionals, and the feasibility of delivering such a trial. RESULTS: Qualitative interviews identified differences in the views of children, young people and their families on a randomised controlled trial and potential barriers to recruitment. A total of 297 participants were screened from 13 centres in just less than 6 months. In practice, all routes of corticosteroid administration were used, and in all subtypes of juvenile idiopathic arthritis. Intra-articular corticosteroid injection was the most common treatment. The questionnaire surveys showed the varying clinical practice across the UK, but established intra-articular corticosteroids as the treatment control for a future trial. The primary outcome of choice for children, young people, their families and health-care professionals was the Juvenile Arthritis Disease Activity Score, 71-joint count. However, results from the feasibility study showed that, owing to missing blood test data, the clinical Juvenile Arthritis Disease Activity Score should be used. The Juvenile Arthritis Disease Activity Score, 71-joint count, and the clinical Juvenile Arthritis Disease Activity Score are composite disease activity scoring systems for juvenile arthritis. Two final trial protocols were established for a future randomised controlled trial. LIMITATIONS: Fewer clinics were included in this feasibility study than originally planned, limiting the ability to draw strong conclusions about these units to take part in future research. CONCLUSIONS: A definitive randomised controlled trial is likely to be feasible based on the findings from this study; however, important recommendations should be taken into account when planning such a trial. FUTURE WORK: This mixed-methods study has laid down the foundations to develop the evidence base in this area and conducting a randomised control trial to compare different corticosteroid induction regimens in children and young people with juvenile idiopathic arthritis is likely to be feasible. STUDY REGISTRATION: Current Controlled Trials ISRCTN16649996. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 36. See the NIHR Journals Library website for further project information.

ABOUT JUVENILE IDIOPATHIC ARTHRITIS: Juvenile idiopathic arthritis refers to a group of conditions that cause inflammation and damage of the joints, starting in children and young people aged < 16 years. Treatments include anti-inflammatory medicines, disease-modifying/biologic medicines and corticosteroids. Young people often require corticosteroids at the start of their treatment, or in a flare with worsening inflammation, to get their juvenile idiopathic arthritis under control. A short course of corticosteroids can help and can be given by injection into the joint, through a drip into a vein, by injection into the muscle or in the form of tablets or liquid to be taken orally. Although they have been used for decades, there is no research to show the best way(s) of giving corticosteroids. STUDY AIMS: The study aimed to (1) agree on what corticosteroid treatments to compare in a treatment trial and the best way to measure changes in juvenile idiopathic arthritis to evaluate a quick-acting treatment and (2) find out if there are enough young people with active juvenile idiopathic arthritis in the UK to be included in such a study. METHODS: Published research on corticosteroids in juvenile idiopathic arthritis was reviewed. Health-care professionals were asked how they choose which corticosteroids to use and which method of administration to use. Interviews were carried out with children and young people and their families to (1) consider the design of a study comparing corticosteroid routes, (2) identify outcomes important to them and (3) determine whether or not they would be willing to take part in a future study. A 3-month feasibility study was carried out to collect details of children and young people with active juvenile idiopathic arthritis before and after corticosteroid treatment to measure improvements in juvenile idiopathic arthritis activity, and to see whether or not a larger study would be possible. FINDINGS: This study showed that corticosteroids are used in different ways across the UK. The views of children, young people and their families must be taken into account when designing a future study. This study calculated the number of young people who would be needed to take part in the future, showing that it would be possible to do a larger study that compared different corticosteroid treatments, which would help everyone to understand the best way to use corticosteroids.

The paediatric global musculoskeletal task force - 'towards better MSK health for all'.

There is increasing concern about the emerging global non-communicable diseases (NCDs) burden. The focus has mainly been on NCDs in adults but it is important that MSK morbidity in both children and adults is included in strategic planning. There have been considerable advances in the understanding and treatment options for children and young people (CYP) and clinical outcomes are improving for those who can access such high quality care. However vast inequity exists and there are many CYP who live in areas of the world with high burden of health care challenges, compounded by paucity of specialist care and limited access to treatments. The Paediatric Global Musculoskeletal Task Force aims to raise awareness about unmet needs for CYP with MSK conditions, promotion of MSK health through lifestyle and the avoidance of injury. We aim to leverage change through 'working together better'.

Global prevalence estimates of three chronic musculoskeletal conditions: club foot, juvenile idiopathic arthritis and juvenile systemic lupus erythematosus.

BACKGROUND: Musculoskeletal (MSK) conditions are a major source of morbidity and disability. There is a lack of global comparable data on the burden of MSK conditions in children and young people. Our aim was to estimate the global prevalence of three MSK conditions - Talipes Equinovarus (Clubfoot), Juvenile Idiopathic Arthritis (JIA) and Juvenile Systemic Lupus Erythematosus (JSLE). METHODS: Using reported prevalence rates, age-stratified population data within the World Bank Data Bank in 2017 and United Nations country classification, we estimated the prevalence of these MSK conditions in < 5 year olds (clubfoot) and < 16 year olds (JIA and JSLE) across the world. RESULTS: We estimated that in 2017, there were ~ 675,061 < 5 year olds with clubfoot among 675,100,000 < 5 year olds, ~ 2,069,246 < 16 year olds with JIA and ~ 206,931 < 16 year olds with JSLE per 2,069,000,000 < 16 year olds, totalling ~ 2,951,238 with one of these conditions. Disease prevalence was greatest in Asia (South Asia), followed by Africa, Americas, Europe and Oceania. CONCLUSIONS: An estimated 3 million children and young people globally are currently living with either clubfoot, JIA or JSLE; many in Asia and Africa. Further work is needed urgently to engage with global stakeholders to work together to improve access to effective care for the many who are affected and reduce the otherwise adverse lifelong impact on their health, quality of life and the impact on society.

The European network for care of children with paediatric rheumatic diseases: care across borders.

OBJECTIVES: To provide an overview of the paediatric rheumatology (PR) services in Europe, describe current delivery of care and training, set standards for care, identify unmet needs and inform future specialist service provision. METHODS: An online survey was developed and presented to national coordinating centres of the Paediatric Rheumatology International Trials Organisation (PRINTO) (country survey) and to individual PR centres (centre and disease surveys) as a part of the European Union (EU) Single Hub and Access point for paediatric Rheumatology in Europe project. The survey contained components covering the organization of PR care, composition of teams, education, health care and research facilities and assessment of needs. RESULTS: Response rates were 29/35 (83%) for country surveys and 164/288 (57%) for centre surveys. Across the EU, approximately one paediatric rheumatologist is available per million population. In all EU member states there is good access to specialist care and medications, although biologic drug availability is worse in Eastern European countries. PR education is widely available for physicians but is insufficient for allied health professionals. The ability to participate in clinical trials is generally high. Important gaps were identified, including lack of standardized clinical guidelines/recommendations and insufficient adolescent transition management planning. CONCLUSION: This study provides a comprehensive description of current specialist PR service provision across Europe and did not reveal any major differences between EU member states. Rarity, chronicity and complexity of diseases are major challenges to PR care. Future work should facilitate the development, dissemination and implementation of standards of care, treatment and service recommendations to further improve patient-centred health care across Europe.

The development and assessment of biological treatments for children.

The development of biological agents with specific immunological targets has revolutionized the treatment of a wide variety of paediatric diseases where traditional immunosuppressive agents have been partly ineffective or intolerable. The increasing requirement for pharmaceutical companies to undertake paediatric studies has provided impetus for studies of biologics in children. The assessment of biological agents in children to date has largely relied upon randomized controlled trials using a withdrawal design, rather than a parallel study design. This approach has been largely used due to ethical concerns, including use of placebo treatments in children with active chronic disease, and justified on the basis that treatments have usually already undergone robust assessment in related adult conditions. However, this study design limits the reliability of the data and can confuse the interpretation of safety results. Careful ongoing monitoring of safety and efficacy in real-world practice through national and international biologics registries and robust reporting systems is crucial. The most commonly used biological agents in children target tumour necrosis factor-α, interleukin-1, interleukin-6 and cytotoxic lymphocyte-associated antigen-4. These agents are most frequently used in paediatric rheumatic diseases. This review discusses the development and assessment of biologics within paediatric rheumatology with reference to the lessons learned from use in other subspecialties.

The association between low socioeconomic status with high physical limitations and low illness self-perception in patients with juvenile idiopathic arthritis: results from the Childhood Arthritis Prospective Study.

OBJECTIVE: To examine the association between socioeconomic status (SES) and delay to a pediatric rheumatology clinic, disease severity, and illness perception in patients with juvenile idiopathic arthritis in England. METHODS: Using the Index of Multiple Deprivation, 923 consecutive children from the Childhood Arthritis Prospective Study were assigned to SES groups: high-SES (19.1%), middle-SES (44.5%), or low-SES (36.4%). At baseline, disease activity was assessed, and the Childhood Health Assessment Questionnaire (C-HAQ), the Illness Perception Questionnaire, and the Child Health Questionnaire, version Parent Form 50, were completed. Linear median regression analyses or zero-inflated negative binominal (ZINB) regression analyses were used. RESULTS: Delay to first pediatric rheumatology consultation was the same between the 3 SES groups. Although disease activity scores assessed by the pediatric rheumatologist did not differ between the 3 SES groups, persons in the low-SES group recorded higher C-HAQ scores compared to the high-SES group (zero-inflated part of ZINB odds ratio 0.28 [95% confidence interval (95% CI) 0.14, 0.55], count part of ZINB ß 0.26 [95% CI 0.05, 0.48]). Parents with low SES also reported more often that their children's school work or activities with friends had been limited. Furthermore, the low-SES group had a worse perception about the consequences of the disease and the effect of treatment than those in the high-SES group. CONCLUSION: Patients from a low-SES background report more problems with daily activities and have a lower perception of the consequences of the disease than patients from a high-SES background, warranting special attention from a multidisciplinary team.

Assessment of musculoskeletal abnormalities in children with mucopolysaccharidoses using pGALS.

BACKGROUND: Children with mucopolysaccharidoses (MPS) often have musculoskeletal (MSK) abnormalities. Paediatric Gait, Arms, Legs, and Spine (pGALS), is a simple MSK assessment validated in school-age children to detect abnormal joints. We aimed to identify MSK abnormalities in children with MPS performing pGALS. METHODS: Videos of children with a spectrum of MPS performing pGALS were analysed. A piloted proforma to record abnormalities for each pGALS manoeuvre observed in the videos (scored as normal/abnormal/not assessable) was used by three observers blinded to MPS subtype. Videos were scored independently and rescored for intra- and inter-observer consistency. Data were pooled and analysed. RESULTS: Eighteen videos of children [12 boys, 6 girls, median age 11 years (4-19)] with MPS (13 type I [5 Hurler, 8 attenuated type I]; 4 type II; 1 mannosidosis) were assessed. The most common abnormalities detected using pGALS were restrictions of the shoulder, elbow, wrist, jaw (>75% cases), and fingers (2/3 cases). Mean intra-observer Κ 0.74 (range 0.65-0.88) and inter-observer Κ 0.62 (range 0.51-0.77). Hip manoeuvres were not clearly demonstrated in the videos. CONCLUSIONS: In this observational study, pGALS identifies MSK abnormalities in children with MPS. Restricted joint movement (especially upper limb) was a consistent finding. Future work includes pGALS assessment of the hip and testing pGALS in further children with attenuated MPS type I. The use of pGALS and awareness of patterns of joint involvement may be a useful adjunct to facilitate earlier recognition of these rare conditions and ultimately access to specialist care.

Agreement between proxy and adolescent assessment of disability, pain, and well-being in juvenile idiopathic arthritis.

OBJECTIVES: Adolescents with juvenile idiopathic arthritis have demonstrated substantial disagreement with their proxy's assessment of their disability, pain, and well-being. Our objective was to describe the clinical and psychological factors associated with discordance. STUDY DESIGN: This analysis included 204 proxy-adolescent (median age, 13 years) dyads that completed a Childhood Health Assessment Questionnaire for disability with 100-mm visual analogue scales for pain and well-being. Depressive symptoms in adolescents were measured by the Mood and Feelings Questionnaire and in proxies the General Health Questionnaire. Disagreement was assessed using Bland-Altman plots. Associations with discordance were identified using logistic regression analyses. RESULTS: There was higher agreement for disability (84%) than for pain (71%) and well-being (66%). Regression analyses found no association between age, sex, or disease duration and disagreement. However, relationships between disease activity and disagreement in outcomes were identified. Independent associations were found between increasing Mood and Feelings Questionnaire scores and disagreement in pain and well-being. CONCLUSIONS: Proxy and adolescent reports of pain and well-being are more likely to disagree in those with severe disease. Adolescents who report depressive symptoms are also more likely to disagree with their proxy. The reasons for these are multifactorial, and considerations of both reports are important when assessing outcomes in juvenile idiopathic arthritis.