Enrolment of the first paediatric cohort into the Australian lupus registry and biobank: A single-centre experience.

INTRODUCTION: We aim to report on the feasibility of establishment of the first paediatric cohort as part of the longitudinal database of the Australian Lupus Registry and Biobank (ALRB) and to describe the enrolment data with a focus on clinical characteristics, serological data, treatment strategies and patient/parent-reported outcome measures. METHODS: All patients under the age of 18 years with a diagnosis of systemic lupus erythematosus (SLE) attending the paediatric rheumatology service of a single, tertiary hospital were identified. Patients were enrolled in the ALRB if they met ≥4/11 of the American College of Rheumatology (ACR) 1997 SLE classification criteria or the Systemic Lupus International Collaborating Clinics (SLICC) 2012 classification criteria. Enrolment data including demographics, clinical characteristics, serological profiles, disease activity and damage assessments were recorded. Peds-QL Rheumatology and General Modules were used to assess patient and parent-reported outcomes. RESULTS: Twenty-seven patients were eligible for inclusion, with 26 patients (96%) consenting for enrolment. Twenty-five patients (92%) consented for biobanking. Twenty patients (77%) were female. The median age at enrolment was 16 years (interquartile range (IQR) 13.7, 17.4). The median disease duration from diagnosis was 3.2 years (IQR 1.4, 5.3). Sixteen patients (62%) had synovitis, 16 (62%) had cutaneous involvement, 4 (15%) had serositis, 17 (65%) had haematological involvement and 7 (27%) had renal involvement at enrolment. Nineteen patients (73%) were prescribed at least two disease-modifying anti-rheumatic medications (DMARDs). Hydroxychloroquine (n = 22, 85%) and mycophenolate mofetil (n = 9, 35%) were the most commonly prescribed DMARDs. The median SLEDAI-2K score was 2 (IQR 2, 4). Six patients (23%) had active disease (SLEDAI-2K ≥6) at enrolment. Three patients (11.5%) had reported damage using the SLICC/ACR Damage Index. Twenty-three children (88%) and eighteen parents (69%) completed the Paediatric Quality of Life Inventory. Quality of life scores reported across domains of physical, emotional, social and school functioning at enrolment were comparable to previously studied paediatric cohorts with SLE and other chronic diseases. CONCLUSION: We have established our centre as the first paediatric participating site of the ALRB, providing contemporary data on the clinical characteristics, serological profile and health-related quality of life outcomes of Australian children with SLE. Paediatric involvement with this national registry will provide a unique perspective for future clinical and scientific research. Collection of Australian-specific paediatric longitudinal data will also enable a broader understanding of SLE within a multicultural Australian population.

Methotrexate for juvenile idiopathic arthritis.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood. Methotrexate has broad immunomodulatory properties and is the most commonly used disease-modifying antirheumatic drug (DMARD). This is an update of a 2001 Cochrane review. It supports a living guideline for children and young people with JIA. OBJECTIVES: To assess the benefits and harms of methotrexate for children and young people with juvenile idiopathic arthritis. SEARCH METHODS: The Australian JIA Living Guideline Working Group created a registry of all randomised controlled trials (RCTs) of JIA by searching CENTRAL, MEDLINE, Embase, and trials registries. The date of the most recent search of online databases was 1 February 2023. SELECTION CRITERIA: We searched for RCTs that compared methotrexate with placebo, no treatment, or another DMARD (with or without concomitant therapies) in children and young people (aged up to 18 years) with JIA. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. The main comparison was methotrexate versus placebo. Our outcomes were treatment response, sustained clinically inactive disease, function, pain, participant global assessment of well-being, serious adverse events, and withdrawals due to adverse events. We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: We identified three new trials in this update, bringing the total number of included RCTs to five (575 participants). Three trials evaluated oral methotrexate versus placebo, one evaluated methotrexate plus intra-articular glucocorticoid (IAGC) therapy versus IAGC therapy alone, and one evaluated methotrexate versus leflunomide. Doses of methotrexate ranged from 5 mg/m2/week to 15 mg/m2/week in four trials, and participants in the methotrexate group of the remaining trial received 0.5 mg/kg/week. Trial size varied from 31 to 226 participants. The average age of participants ranged from four to 10 years. Most participants were females and most had nonsystemic JIA. The study that evaluated methotrexate plus IAGC therapy versus IAGC therapy alone recruited children and young people with the oligoarticular disease subtype of JIA. Two placebo-controlled trials and the trial of methotrexate versus leflunomide were adequately randomised and blinded, and likely not susceptible to important biases. One placebo-controlled trial may have been susceptible to selection bias due to lack of adequate reporting of randomisation methods. The trial investigating the addition of methotrexate to IAGC therapy was susceptible to performance and detection biases. Methotrexate versus placebo Methotrexate compared with placebo may increase the number of children and young people who achieve treatment response up to six months (absolute difference of 163 more per 1000 people; risk ratio (RR) 1.67, 95% confidence interval (CI) 1.21 to 2.31; I2 = 0%; 3 trials, 328 participants; low-certainty evidence). However, methotrexate compared with placebo may have little or no effect on pain as measured on an increasing scale of 0 to 100 (mean difference (MD) -1.10 points, 95% CI -9.09 to 6.88; 1 trial, 114 participants), improvement in participant global assessment of well-being (absolute difference of 92 more per 1000 people; RR 1.23, 95% CI 0.88 to 1.72; 1 trial, 176 participants), occurrence of serious adverse events (absolute difference of 5 fewer per 1000 people; RR 0.63, 95% CI 0.04 to 8.97; 3 trials, 328 participants), and withdrawals due to adverse events (RR 3.46, 95% CI 0.60 to 19.79; 3 trials, 328 participants) up to six months. We could not estimate the absolute difference for withdrawals due to adverse events because there were no withdrawals in the placebo group. All outcomes were reported within six months of randomisation. We downgraded the certainty of the evidence to low for all outcomes due to indirectness (suboptimal dosing of methotrexate and diverse outcome measures) and imprecision (few participants and low event rates). No trials reported function or the number of participants with sustained clinically inactive disease. Serious adverse events included liver derangement, abdominal pain, and inadvertent overdose. Methotrexate plus intra-articular corticosteroid therapy versus intra-articular corticosteroid therapy alone Methotrexate plus IAGC therapy compared with IAGC therapy alone may have little or no effect on the probability of sustained clinically inactive disease or the rate of withdrawals due to adverse events up to 12 months in children and young people with the oligoarticular subtype of JIA (low-certainty evidence). We could not calculate the absolute difference in withdrawals due to adverse events because there were no withdrawals in the control group. We are uncertain if there is any difference between the interventions in the risk of severe adverse events, because none were reported. The study did not report treatment response, function, pain, or participant global assessment of well-being. Methotrexate versus an alternative disease-modifying antirheumatic drug Methotrexate compared with leflunomide may have little or no effect on the probability of treatment response or on function, participant global assessment of well-being, risk of serious adverse events, and rate of withdrawals due to adverse events up to four months. We downgraded the certainty of the evidence for all outcomes to low due to imprecision. The study did not report pain or sustained clinically inactive disease. AUTHORS' CONCLUSIONS: Oral methotrexate (5 mg/m2/week to 15 mg/m2/week) compared with placebo may increase the number of children and young people achieving treatment response but may have little or no effect on pain or participant global assessment of well-being. Oral methotrexate plus IAGC injections compared to IAGC injections alone may have little or no effect on the likelihood of sustained clinically inactive disease among children and young people with oligoarticular JIA. Similarly, methotrexate compared with leflunomide may have little or no effect on treatment response, function, and participant global assessment of well-being. Serious adverse events due to methotrexate appear to be rare. We will update this review as new evidence becomes available to inform the living guideline.

The transition process for paediatric rheumatology clinic patients at a single tertiary paediatric rheumatology centre in Australia.

AIM: This study aimed to examine the transition process of paediatric rheumatology patients from the Monash Children's Hospital (MCH) in Melbourne in order to identify areas that could be improved. METHODS: Retrospective review of clinical data from the rheumatology database of paediatric rheumatology patients eligible for transition between January 2015 and September 2020. RESULTS: One hundred and sixty-five patients were included; 57 patients were transitioned. Of patients transitioned to an adult service, 38 (88%) were on medication and 14 (33%) had active disease. All patients transitioned to the general practitioner (GP) had inactive disease off medication. Juvenile idiopathic arthritis (JIA) (non-systemic) was the most common diagnosis in patients transitioned. The mean age at which transition was first discussed was 18.0 years; the first referral was made at a mean of 18.3 years. The mean age at the first adult appointment was 18.5 years. Thirty-nine (91%) patients had a referral completed and 8 (19%) had a transfer letter. Thirteen (93%) patients transferred to the GP had a transfer letter. Transfer documents to an adult public rheumatology service rated 4.3 for quality, compared to 5.5 to the GP. Transfer of care was confirmed in 40 (93%) patients transitioned to an adult service; however, correspondence was available for only 3 (7%). CONCLUSION: Although the transition process at MCH was adequate, it could be improved through earlier discussion of the process and improved referrals and documentation. A readiness-to-transfer checklist and a young adult clinic have the potential to improve the process of transition to adult rheumatology care.

Patterns and rates of confirmed transfer of care of patients with juvenile idiopathic arthritis at a tertiary paediatric rheumatology centre.

BACKGROUND: Disease activity in juvenile idiopathic arthritis (JIA) commonly persists into adulthood. Transfer of JIA patients to adult healthcare services can be challenging, with prior studies showing poor rates of success. AIMS: This audit sought to examine characteristics of patients undergoing transfer of care within the rheumatology unit at the Royal Children's Hospital in Melbourne, with the aim of identifying areas for improvement. Specifically, we sought to determine the rate at which confirmation of established care with an adult service (confirmed transfer of care) was documented in the patient chart. METHODS: Patients with a diagnosis of JIA who turned 18 years of age between 2012 and 2019 were identified. A chart review was undertaken to collect relevant data. RESULTS: One hundred and seventy-seven patients were identified. In all, 64% (114/177) were referred for adult care. The commonest JIA subtypes referred were seronegative polyarticular (35/114; 30.7%) and oligoarticular JIA (22/114; 19.3%). Documentation of confirmed transfer of care occurred in 62.3% (71/114), with correspondence received from adult services in 49.1% (56/114). There was no difference in rate of return correspondence from public versus private providers (45% vs 53.8%; P = 0.38). The use of 'backstop appointments' was more likely in those with confirmed transfer of care (66% vs 30%; P = 0.0002). CONCLUSIONS: Lack of confirmed transfer of care for JIA patients is common and carries a risk of suboptimal outcomes. Strategies to improve communication with adult services, the routine use of 'backstop' appointments and vigilance regarding potential loss to follow up at the time of transfer would minimise this risk.

Rheumatology and the adolescent patient.

BACKGROUND: Adolescence can be a time when rheumatological conditions present to the general practitioner for diagnosis and management. Diagnosis of rheumatic disease during adolescence and earlier childhood often brings additional challenges such as those relating to body image, schooling and recreational activities, friendships and relationships, compliance with medications and independence with healthcare needs. OBJECTIVE: This article highlights rheumatological conditions that have relevance during adolescence and describes the approach to the history, examination and investigation of young people with rheumatic disease. Some common management issues that may arise when assessing adolescent patients in the primary care setting, including indications for referral to a rheumatologist, are outlined. DISCUSSION: The transition from one of dependence to self-management is a complex but important process as many adolescents with rheumatic disease will have persistent disease activity or ongoing sequelae continuing into their adulthood.

Three- and five-year outcomes of an inception cohort of Australian children with juvenile idiopathic arthritis.

BACKGROUND: To describe the 3- and 5-year outcomes of an inception cohort of Australian children with JIA for whom 1-year outcomes have previously been published. METHODS: Data regarding clinical outcomes of the original cohort of 134 patients at 3 and 5 years were sought. Relevant clinical features and medication exposures entered prospectively into an electronic record were collected and analyzed using descriptive statistics. RESULTS: Data were available for 110 and 98 patients at 3 and 5 years, respectively. The proportion of patients with active joints progressively decreased from 34% at 12 months to 21% at 3 years and 16% at 5 years. Cumulative exposure to methotrexate increased between 3 and 5 years (75%-80%), however, point prevalence use decreased (45%-41%). Cumulative exposure and point prevalence use of bDMARDS both increased between 3 and 5 years; 30%-42% and 29%-33%, respectively. Thirty-five percent of patients had inactive joint disease off medications at 5 years, which occurred most frequently in patients with sJIA and oligoarthritis. CONCLUSION: Five-year outcomes of Australian children with JIA are good, with only a small minority having ongoing active joint disease at 5 years. bDMARDS play an increasing role in management over time; however, methotrexate use remains significant. A majority of children remain on medications at 5 years.

Microgeodic disease in an infant.

We describe an infant presenting with intermittent discolouration and swelling of her fingers and toes occurring with changes in ambient temperature. Extensive investigations revealed raised inflammatory markers as well as sclerotic lesions within the phalanges and diffuse marrow oedema. Infectious and inflammatory causes were considered and excluded based on the clinical presentation and investigation findings. The persistence of symptoms prompted further investigation with MRI. Correlation of the MRI findings with previous case reports resulted in a diagnosis of microgeodic disease-an uncommon, self-limiting condition thought to be due to cold-induced vasospasm leading to avascular necrosis of the bone.

Modified Delphi study to identify priority clinical questions for the Australian living guidelines for the management of Juvenile Idiopathic Arthritis.

BACKGROUND: Juvenile Idiopathic Arthritis (JIA) is the most common rheumatic inflammatory disease in childhood. Optimal management requires clinicians to be up to date with the rapidly evolving evidence base. 'Living' evidence-based clinical practice guidelines, which integrate new evidence as soon as it is available, are a novel method to enhance the translation of research into practice. To determine the most relevant questions that should be prioritised in national Australian JIA living guidelines, we invited Australian and New Zealand paediatric rheumatologists and other relevant health professionals to identify and rank their most important questions in order of priority. METHODS: All 47 members of the Australian Paediatric Rheumatology Group (APRG) were invited to participate in a modified Delphi study comprising two rounds. The first round identified demographic information of respondents, current attitudes to guideline use and invited submission of priority management questions. The second round asked respondents to rank 27 collated and refined questions identified in round one in order of priority. RESULTS: There were 29 (62%) and 28 (60%) responses to the first and second survey rounds respectively. About two thirds were rheumatologists or trainees (66, 68%), nearly half had more than 10 years of experience (45, 46%) and practice setting was largely hospital (79, 86%) and urban (86, 75%). Most respondents used clinical guidelines in their practice (72% sometimes, 24% often), most frequently American College of Rheumatology (ACR) (66%) and European Alliance of Associations for Rheumatology (EULAR) (59%) guidelines. Reported barriers to guideline use included that they are not up to date and access difficulties. Most respondents (83%) considered Australian guidelines were necessary and two-thirds indicated they would use them if integrated into practice software. The highest ranked topics were down-titration and discontinuation of disease modifying anti-rheumatic drugs (ranked first), best outcome measures (second) and treatment targets in JIA (third). CONCLUSIONS: There is strong clinician support for the development of Australian living guidelines for JIA. Consensus was reached on the ten top-ranked priority questions. Our guidelines will develop evidence-based recommendations for these high priority questions that will be updated in real time as needed to facilitate rapid translation of evidence into clinical practice.

Exploring the Intersection of Isolated-CNS Hemophagocytic Lymphohistiocytosis and Pediatric Chronic Lymphocytic Inflammation With Pontine Perivascular Enhancement Responsive to Steroids.

CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) is an extremely rare neurologic inflammatory condition. Fewer than 10 pediatric cases have been described.Debate persists as to whether it is a distinct disease or a clinical, radiologic, and histologic phenotype evolving into another disorder. We propose that CLIPPERS may be a clinical manifestation of an underlying state of immune-dysregulation.We describe the case of the youngest known report of CLIPPERS, an 18-month-old infant from Melbourne, Australia. Reviewing the literature for all reported pediatric cases, we identified that robust investigation and whole exome sequencing was underutilized and proposed diagnostic criteria were frequently unmet. Particular focus should be paid to genes known to cause familial hemophagocytic lymphohistiocytosis (HLH), with the CLIPPERS phenotype manifesting as a form of isolated central nervous system (CNS)-HLH in some patients. Curative treatment options such as hematopoietic stem cell transplantation may be appropriate for some patients and should be considered early.

Juvenile idiopathic arthritis managed in the new millennium: one year outcomes of an inception cohort of Australian children.

BACKGROUND: The advent of new treatments for Juvenile Idiopathic Arthritis (JIA) has prompted interest in systematically studying the outcomes of patients treated in the 'modern era'. Such data provide both benchmarks for assessing local outcomes and important information for use in counselling families of newly diagnosed patients. While data are available for cohorts in Europe and North America, no such data exist for Australian patients. The aim was to examine the demographics, treatment and outcomes at 12 months of an inception cohort of newly diagnosed patients with JIA at a single tertiary referral paediatric rheumatology centre in Australia. METHODS: Retrospective review of prospectively collected data from patients newly diagnosed with JIA between 2010 and 2014 at the Royal Children's Hospital in Melbourne. RESULTS: One hundred thirty four patients were included (62% female). Oligoarthritis was the single largest category of JIA (36%) and rheumatoid factor positive polyarthritis the least common (2%). Undifferentiated JIA accounted for 13% of patients and was the third largest category. Across the cohort 94% received NSAIDs, 53% oral steroids, 62% methotrexate and 15% a biologic DMARD. Intra-articular steroids were used in 62%, most commonly in the oligoarticular subtype (94%). 95% of patients achieved a joint count of zero at a median of 4.1 months, however flares occurred in 42%. At 12 months 65% had no active joint disease, though more than half remained on medication. CONCLUSION: Australian children with JIA managed in the modern era have similar characteristics and achieve short term outcomes comparable to cohorts in Europe and North America, with high rates of joint remission in the first 12 months of follow-up but with a significant relapse rate and requirement for ongoing medication.