Development of a national audit tool for juvenile idiopathic arthritis: a BSPAR project funded by the Health Care Quality Improvement Partnership.

Objective: Timely access to holistic multidisciplinary care is the core principle underpinning management of juvenile idiopathic arthritis (JIA). Data collected in national clinical audit programmes fundamentally aim to improve health outcomes of disease, ensuring clinical care is equitable, safe and patient-centred. The aim of this study was to develop a tool for national audit of JIA in the UK. Methods: A staged and consultative methodology was used across a broad group of relevant stakeholders to develop a national audit tool, with reference to pre-existing standards of care for JIA. The tool comprises key service delivery quality measures assessed against two aspects of impact, namely disease-related outcome measures and patient/carer reported outcome and experience measures. Results: Eleven service-related quality measures were identified, including those that map to current standards for commissioning of JIA clinical services in the UK. The three-variable Juvenile Arthritis Disease Activity Score and presence/absence of sacro-iliitis in patients with enthesitis-related arthritis were identified as the primary disease-related outcome measures, with presence/absence of uveitis a secondary outcome. Novel patient/carer reported outcomes and patient/carer reported experience measures were developed and face validity confirmed by relevant patient/carer groups. Conclusion: A tool for national audit of JIA has been developed with the aim of benchmarking current clinical practice and setting future standards and targets for improvement. Staged implementation of this national audit tool should facilitate investigation of variability in levels of care and drive quality improvement. This will require engagement from patients and carers, clinical teams and commissioners of JIA services.

Infection-Related Death among Persons with Refractory Juvenile Idiopathic Arthritis.

Severe infections are emerging as major risk factors for death among children with juvenile idiopathic arthritis (JIA). In particular, children with refractory JIA treated with long-term, multiple, and often combined immunosuppressive and antiinflammatory agents, including the new biological disease-modifying antirheumatic drugs (DMARDs), are at increased risk for severe infections and death. We investigated 4 persons with JIA who died during 1994-2013, three of overwhelming central venous catheter-related bacterial sepsis caused by coagulase-negative Staphylococus or α-hemolytic Streptococcus infection and 1 of disseminated adenovirus and Epstein-Barr virus infection). All 4 had active JIA refractory to long-term therapy with multiple and combined conventional and biological DMARDs. Two died while receiving high-dose systemic corticosteroids, methotrexate, and after recent exposure to anti-tumor necrosis factor-α biological DMARDs, and 2 during hematopoietic stem cell transplantation procedure. Reporting all cases of severe infections and especially deaths in these children is of paramount importance for accurate surveillance.

Mucocutaneous manifestations in a UK national cohort of juvenile-onset systemic lupus erythematosus patients.

OBJECTIVE: To determine whether mucocutaneous manifestations are associated with major organ involvement in a UK national cohort of juvenile-onset SLE (JSLE) patients. METHODS: JSLE patients (n = 241) from 15 different centres whose diagnosis fulfilled four or more of the ACR criteria were divided into two groups: those with at least one ACR mucocutaneous criterion (ACR skin feature positive) and those without (ACR skin feature negative) at diagnosis. The relative frequency of skin involvement was described by the paediatric adaptation of the 2004 British Isles Lupus Assessment Group (pBILAG-2004) index. RESULTS: One hundred and seventy-nine patients (74%) had ACR-defined skin involvement with no significant demographic differences compared with those without. ACR skin feature negative patients showed greater haematological (84% vs 67%), renal (43% vs 26%) (P < 0.05) and neurological (16% vs 4%) involvement (P = 0.001). Forty-two per cent of ACR skin feature negative patients had skin involvement using pBILAG-2004, which included maculopapular rash (17%), non-scaring alopecia (15%), cutaneous vasculitis (12%) and RP (12%). ACR skin feature negative patients with moderate to severe skin involvement by pBILAG-2004 showed greater renal and haematological involvement at diagnosis and over the follow-up period (P < 0.05). Higher immunosuppressive drug use in the skin feature negative group was demonstrated. CONCLUSION: Patients who fulfil the ACR criteria but without any of the mucocutaneous criteria at diagnosis have an increased risk of major organ involvement. The pBILAG-2004 index has shown that other skin lesions may go undetected using the ACR criteria alone, and these lesions show a strong correlation with disease severity and major organ involvement.

Short Message Service Reminder Nudge for Parents and Influenza Vaccination Uptake in Children and Adolescents With Special Risk Medical Conditions: The Flutext-4U Randomized Clinical Trial.

Importance: Children with chronic medical conditions are at increased risk of severe influenza. Uptake of influenza vaccination in children and adolescents with these identified special risk medical conditions (SRMCs) is suboptimal. Objective: To assess the effectiveness of Flutext-4U, a parent short message service (SMS) reminder nudge intervention, in increasing influenza immunization in children and adolescents with SRMCs. Design, Setting, and Participants: This randomized clinical trial was conducted at a tertiary pediatric hospital in Adelaide, South Australia, from April 15 to September 30, 2021. Children and adolescents aged 6 months to younger than 18 years with SRMCs and a subspecialist outpatient appointment over a 5-month period during the Australian seasonal influenza vaccination season (April-August 2021) were eligible to participate. Follow-up was until September 30, 2021. Interventions: Participants were randomly assigned (1:1 ratio) to control: clinician nudges (hospital vaccine availability, ease of access, and recommendation from hospital subspecialists) or SMS intervention (control conditions plus an additional SMS reminder nudge to parents), with randomization stratified by age group (<5 years, 5-14 years, or >14 to <18 years). Main Outcomes and Measures: The primary outcome was influenza vaccination, as confirmed by the Australian Immunisation Register. Results: A total of 600 participants (intervention group: 298 [49.7%]; mean [SD] age, 11.5 [4.6] years; 162 female participants [54.4%]; control group: 302 [50.3%]; mean [SD] age, 11.4 [4.7] years; 155 female participants [51.3%]) were included. Influenza vaccination was 38.6% (113 of 293) in the SMS intervention group compared with 26.2% (79 of 302) in the control group (adjusted odds ratio [aOR], 1.79; 95% CI, 1.27-2.55; P = .001). Time to vaccine receipt was significantly lower among SMS participants (adjusted hazard ratio, 1.67; 95% CI, 1.25-2.22; P < .001). For participants randomly assigned by June 15, a significantly greater proportion receiving the SMS intervention were vaccinated during the optimal delivery period April to June 30 (SMS group: 40.0% [76 of 190] vs 25.4% [50 of 197]; aOR, 1.97; 95% CI, 1.28-3.06; P = .002). Conclusions and Relevance: Results of this randomized clinical trial suggest that an additional SMS reminder nudge for parents delivered in the tertiary care hospital setting to children and adolescents with SMRCs resulted in higher influenza vaccine uptake compared with clinician nudges alone. Trial Registration: ANZCTR Identifier: ACTRN12621000463875.

Heart transplantation following myocardial infarction due to Takayasu's arteritis.

We report a 14-yr-old girl who presented with cardiogenic shock because of compression of the left main coronary artery secondary to Takayasu's arteritis. The patient required cardiac transplantation with hemi-arch replacement at the time of transplant because of ascending aortitis. To our knowledge, this is the first case of cardiac transplantation in Takayasu's arteritis to be reported in the literature.

Using provider-parent strategies to improve influenza vaccination in children and adolescents with special risk medical conditions: a randomised controlled trial protocol.

INTRODUCTION: Influenza immunisation is a highly cost-effective public health intervention. Despite a comprehensive National Immunisation Program, influenza vaccination in children and adolescents with special risk medical conditions (SRMCs) is suboptimal. Flutext-4U is an innovative, multi-component strategy targeting paediatric hospitals, general practice and parents of children and adolescents with SRMC. The Flutext-4U study aims to assess the impact of Flutext-4U to increase influenza immunisation in children and adolescents with SRMC. METHODS AND ANALYSIS: This is a randomised controlled trial involving parents of children and adolescents (aged >6 months to <18 years) with SRMC receiving tertiary care at the Women's and Children's Hospital (WCH), Adelaide, South Australia, who are eligible for funded influenza immunisation with a hospital appointment between the start of the seasonal influenza vaccination season and 31 July 2021, their treating general practitioners (GPs), and WCH paediatric specialists.Parents (of children/adolescents with SRMC) are randomised (1:1 ratio) to standard care plus intervention (SMS reminder messages to parents; reminders (written correspondence) for their child's GP from the hospital's Paediatric Outpatients Department) or standard care (hospital vaccine availability, ease of access and reminders for WCH subspecialists) with randomisation stratified by age-group (<5, 5-14, >14 to <18 years).The primary outcome is influenza vaccination, as confirmed by the Australian Immunisation Register.The proportion vaccinated (primary outcome) will be compared between randomised groups using logistic regression, with adjustment made for age group at randomisation. The effect of treatment will be described using an OR with a 95% CI. ETHICS AND DISSEMINATION: The protocol and all study materials have been reviewed and approved by the Women's and Children's Health Network Human Research Ethics Committee (HREC/20/WCHN/5). Results will be disseminated via peer-reviewed publication and at scientific meetings, professional and public forums. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12621000463875).

Treatment of primary angiitis of the central nervous system in childhood with mycophenolate mofetil.

OBJECTIVE: To assess the use of mycophenolate mofetil (MMF) in the treatment of refractory primary angiitis of the CNS in childhood (cPACNS). METHODS: A retrospective chart review was performed in patients with cPACNS who were treated with MMF following failure of a combination of corticosteroids and another immunosuppressant. RESULTS: Three patients from two centres were included in this study. The age of onset of disease was 5, 6 and 9 years. All the patients improved when treated with MMF, such that the dose of corticosteroids could be weaned or stopped. CONCLUSIONS: MMF should be considered for maintenance treatment in the management of patients with cPACNS refractory to the combination of corticosteroids and first-line immunosuppressive agents.

Intracerebral large artery disease in Aicardi-Goutières syndrome implicates SAMHD1 in vascular homeostasis.

AIM: To describe a spectrum of intracerebral large artery disease in Aicardi-Goutières syndrome (AGS) associated with mutations in the AGS5 gene SAMHD1. METHOD: We used clinical and radiological description and molecular analysis. RESULTS: Five individuals (three males, two females) were identified as having biallelic mutations in SAMHD1 and a cerebral arteriopathy in association with peripheral vessel involvement resulting in chilblains and ischaemic ulceration. The cerebral vasculopathy was primarily occlusive in three patients (with terminal carotid occlusion and basal collaterals reminiscent of moyamoya syndrome) and aneurysmal in two. Three of the five patients experienced intracerebral haemorrhage, which was fatal in two individuals. Post-mortem examination of one patient suggested that the arteriopathy was inflammatory in origin. INTERPRETATION: Mutations in SAMHD1 are associated with a cerebral vasculopathy which is likely to have an inflammatory aetiology. A similar disease has not been observed in patients with mutations in AGS1 to AGS4, suggesting a particular role for SAMHD1 in vascular homeostasis. Our report raises important questions about the management of patients with mutations in SAMHD1.

Allogeneic hematopoietic stem cell transplantation for severe, refractory juvenile idiopathic arthritis.

Patients with juvenile idiopathic arthritis (JIA) can experience a severe disease course, with progressive destructive polyarthritis refractory to conventional therapy with disease-modifying antirheumatic drugs including biologics, as well as life-threatening complications including macrophage activation syndrome (MAS). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative immunomodulatory strategy for patients with such refractory disease. We treated 16 patients in 5 transplant centers between 2007 and 2016: 11 children with systemic JIA and 5 with rheumatoid factor-negative polyarticular JIA; all were either refractory to standard therapy, had developed secondary hemophagocytic lymphohistiocytosis/MAS poorly responsive to treatment, or had failed autologous HSCT. All children received reduced toxicity fludarabine-based conditioning regimens and serotherapy with alemtuzumab. Fourteen of 16 patients are alive with a median follow-up of 29 months (range, 2.8-96 months). All patients had hematological recovery. Three patients had grade II-IV acute graft-versus-host disease. The incidence of viral infections after HSCT was high, likely due to the use of alemtuzumab in already heavily immunosuppressed patients. All patients had significant improvement of arthritis, resolution of MAS, and improved quality of life early following allo-HSCT; most importantly, 11 children achieved complete drug-free remission at the last follow-up. Allo-HSCT using alemtuzumab and reduced toxicity conditioning is a promising therapeutic option for patients with JIA refractory to conventional therapy and/or complicated by MAS. Long-term follow-up is required to ascertain whether disease control following HSCT continues indefinitely.

Elicitation of expert prior opinion: application to the MYPAN trial in childhood polyarteritis nodosa.

OBJECTIVES: Definitive sample sizes for clinical trials in rare diseases are usually infeasible. Bayesian methodology can be used to maximise what is learnt from clinical trials in these circumstances. We elicited expert prior opinion for a future Bayesian randomised controlled trial for a rare inflammatory paediatric disease, polyarteritis nodosa (MYPAN, Mycophenolate mofetil for polyarteritis nodosa). METHODS: A Bayesian prior elicitation meeting was convened. Opinion was sought on the probability that a patient in the MYPAN trial treated with cyclophosphamide would achieve disease remission within 6-months, and on the relative efficacies of mycophenolate mofetil and cyclophosphamide. Expert opinion was combined with previously unseen data from a recently completed randomised controlled trial in ANCA associated vasculitis. RESULTS: A pan-European group of fifteen experts participated in the elicitation meeting. Consensus expert prior opinion was that the most likely rates of disease remission within 6 months on cyclophosphamide or mycophenolate mofetil were 74% and 71%, respectively. This prior opinion will now be taken forward and will be modified to formulate a Bayesian posterior opinion once the MYPAN trial data from 40 patients randomised 1:1 to either CYC or MMF become available. CONCLUSIONS: We suggest that the methodological template we propose could be applied to trial design for other rare diseases.

Autologous T cell depleted haematopoietic stem cell transplantation in children with severe juvenile idiopathic arthritis in the UK (2000-2007).

UNLABELLED: As part of collaborative multi-centre study started in 2000, 7 children in the UK fulfilled the inclusion criteria for treatment with autologous T cell depleted (TCD) haematopoietic stem cell transplantation (HSCT) for severe juvenile idiopathic arthritis (JIA). Here we report on the outcome and transplant-related complications. OUTCOME: The initial, often dramatic clinical response in all patients was followed in 4 with sustained benefit, including the withdrawal of immunosuppressive and anti-inflammatory treatment, significant catch-up growth and immense improvement of the quality of life during 5-8 years long follow-up. Two patients relapsed within 1-12 months, and one died 4 months post transplant. COMPLICATIONS: Adenovirus reactivation with dissemination was lethal in one patient, whilst Epstein-Barr (EBV) and cytomegalovirus (CMV) reactivation-driven haemophagocytic syndrome responded to antiviral and immunomodulatory treatment in 2 patients. Both the conditioning and the T cell depletion of the graft, leading to severe immunosuppression and prolonged immune system function reconstitution, are the main predisposing factors for potentially life-threatening transplant-related complications. CONCLUSIONS: Autologous TCD HSCT for children with severe JIA results in two-phase response. The initial remission seen in all patients is due to immunosuppressive conditioning. This is followed by sustained drug-free remission in over 50% of patients, which is due to 'immunomodulatory' effects of TCD HSCT. The procedure carries a significant morbidity and mortality risk. However, this risk should be balanced against the risks of life-threatening infections occurring in this very selective group of patients on long-term and combined immunosuppressive and anti-inflammatory therapies. How to correctly identify and appropriately assess the patients in need for autologous TCD HSCT, particularly in relation to optimizing the timing for the procedure in regards to the newly available therapies with different biologic response modifiers, are some of the most important questions awaiting answers from this on-going study.