Towards development of treat to target (T2T) in childhood-onset systemic lupus erythematosus: PReS-endorsed overarching principles and points-to-consider from an international task force.

OBJECTIVES: Application of 'treat-to-target' (T2T) in childhood-onset systemic lupus erythematosus (cSLE) may improve care and health outcomes. This initiative aimed to harmonise existing evidence and expert opinion regarding T2T for cSLE. METHODS: An international T2T Task Force was formed of specialists in paediatric rheumatology, paediatric nephrology, adult rheumatology, patient and parent representatives. A steering committee formulated a set of draft overarching principles and points-to-consider, based on evidence from systematic literature review. Two on-line preconsensus meeting Delphi surveys explored healthcare professionals' views on these provisional overarching principles and points-to-consider. A virtual consensus meeting employed a modified nominal group technique to discuss, modify and vote on each overarching principle/point-to-consider. Agreement of >80% of Task Force members was considered consensus. RESULTS: The Task Force agreed on four overarching principles and fourteen points-to-consider. It was agreed that both treatment targets and therapeutic strategies should be subject to shared decision making with the patient/caregivers, with full remission the preferred target, and low disease activity acceptable where remission cannot be achieved. Important elements of the points-to-consider included: aiming for prevention of flare and organ damage; glucocorticoid sparing; proactively addressing factors that impact health-related quality of life (fatigue, pain, mental health, educational challenges, medication side effects); and aiming for maintenance of the target over the long-term. An extensive research agenda was also formulated. CONCLUSIONS: These international, consensus agreed overarching principles and points-to-consider for T2T in cSLE lay the foundation for future T2T approaches in cSLE, endorsed by the Paediatric Rheumatology European Society.

Non-invasive imaging and clinical skin scores in juvenile localised scleroderma.

OBJECTIVES: To evaluate whether in juvenile localised scleroderma (JLS), non-invasive imaging can differentiate affected from non-affected skin and whether imaging correlates with a validated skin score (Localised Scleroderma Cutaneous Assessment Tool, LoSCAT). METHODS: 25 children with JLS were recruited into a prospective study and a single 'target' lesion selected. High frequency ultrasound (HFUS, measuring skin thickness), infrared thermography (IRT, skin temperature), laser Doppler imaging (LDI, skin blood flow) and multispectral imaging (MSI, oxygenation), were performed at four sites: two of affected skin (centre and inner edge of lesion) and two of non-affected skin (one cm from edge of lesion 'outer' and contralateral non-affected side), at 4 visits at 3 monthly intervals. RESULTS: Differences between affected and non-affected skin were detected with all 4 techniques. Compared with non-affected skin, affected skin was thinner (p< 0.001) with higher temperature (p< 0.001-0.006), perfusion (p< 0.001-0.039) and oxygenation (p< 0.001-0.028). Lesion skin activity (LoSCAT) was positively correlated with centre HFUS (r = 0.32; 95% CI [0.02, 0.61]; p= 0.036) and negatively correlated with centre LDI (r=-0.26; 95% CI [-0.49, -0.04]; p= 0.022). Lesion skin damage was positively correlated with centre and inner IRT (r = 0.43; 95% CI [0.19, 0.67]; p< 0.001, r = 0.36, 95% CI [0.12, 0.59]; p= 0.003, respectively) and with centre and inner LDI (r = 0.37; 95% CI [0.05, 0.69]; p= 0.024, r = 0.41; 95% CI [0.08, 0.74]; p= 0.015, respectively). CONCLUSION: Non-invasive imaging can detect differences between affected and non-affected skin in JLS and may help to differentiate between activity (thicker, less well perfused skin) and damage (thinner, highly perfused skin).

Prospective epidemiological study of juvenile-onset systemic lupus erythematosus in the UK and Republic of Ireland.

OBJECTIVES: The primary objective was to define the incidence of JSLE in children <16 years of age in the UK and Republic of Ireland (ROI). The secondary objective was to describe presenting features, classification criteria, initial management and disease damage in newly presenting JSLE patients. METHODS: A prospective JSLE epidemiological study was undertaken between September 2017 and September 2019 with support of the British Paediatric Surveillance Unit and other professional groups involved in diagnosis and management of JSLE patients. Treating consultants reported all cases of JSLE seen. A follow-up study at 1 year examined management and progression of disease and treatment. RESULTS: There were 124 incident cases included in the final analysis. Incidence was estimated using ACR-1997 classification criteria (0.36/100 000), SLICC-2012 classification criteria (0.41/100 000) and clinician expert opinion (0.46/100 000). A high disease burden was seen, with 71.0% of patients requiring ongoing systemic CS treatment at 1 year; 98.2% receiving immunomodulatory treatment; and 20.4% accruing damage in the year following diagnosis (predominantly neuropsychiatric-related), with substantial involvement from multiple speciality teams. CONCLUSIONS: The minimum UK and ROI incidence of JSLE is between 0.36 and 0.46/100 000, depending on the case definition used. Challenges in classification of patients with JSLE are highlighted, but overall this study supports the use of SLICC-2012 classification criteria. The high levels of disease damage and ongoing CS use 1 year after diagnosis is concerning, highlighting the need for further interventions to improve outcomes in JSLE.

Cardiac pathology and outcomes vary between Kawasaki disease and PIMS-TS.

Overlapping clinical features promoted the discussion of whether Kawasaki disease (KD) and PIMS-TS share pathophysiological features and disease outcomes. Medical records from English patients with KD (2015-02/20, N = 27) and PIMS-TS (02/2020-21, N = 34) were accessed to extract information. Children with PIMS-TS were older and more frequently of minority ethnicity background. They patients more commonly exhibited cytopenias and hyperferritinemia, which associated with diffuse cardiac involvement and functional impairment. In some PIMS-TS cases, cardiac pathology developed late, but outcomes were more favorable. In both, KD and PIMS-TS, baseline coronary diameter was a predictor of outcomes. PIMS-TS treatment more frequently included respiratory and cardiovascular support, and corticosteroids with IVIG. Cardiac involvement in PIMS-TS may be the result of a cytokine storm. Though more severe and diffuse when compared to KD, cardiac involvement of PIMS-TS has a more favorable prognosis, which may, after recovery, mitigate the need for long-term follow up.

Behçet's syndrome in children and young people in the United Kingdom and the Republic of Ireland: a prospective epidemiological study.

OBJECTIVES: To define the incidence and prevalence of Behçet's syndrome (BS) in children and young people (CYP) up to the age of 16 years in the United Kingdom (UK) and Republic of Ireland (ROI). METHODS: A prospective epidemiological study was undertaken with the support of the British Paediatric Surveillance Unit (BPSU) and the British Society of Paediatric Dermatologists (BSPD). Consultants reported anonymised cases of BS seen. A follow-up study at one year examined progression of disease and treatment. RESULTS: Over a two-year period, 56 cases met the International Criteria for Behçet's Disease. For children under 16 years of age, the two-year period prevalence estimate was 4.2 per million (95% CI: 3.2, 5.4) and the incidence was 0.96 per million person years (95% CI: 0.66, 1.41). Mucocutaneous disease was the most common phenotype (56/100%), with ocular (10/56; 17.9%), neurological (2/56; 3.6%) and vascular involvement (3/56; 5.4%) being less common. Median age at onset was 6.34 years and at diagnosis was 11.72 years. There were slightly more female than male children reported (32/56; 55.6%). The majority of cases (85.7%) were white Caucasian. Apart from genital ulcers, which were more common in females, there were no significant differences in frequency of manifestations between male or females, nor between ethnicities. Over 83% of cases had three or more non-primary care healthcare professionals involved in their care. CONCLUSION: BS is extremely rare in CYP in the UK and ROI and most have mucocutaneous disease. Healthcare needs are complex, and coordinated care is key.

Juvenile-onset Behçet's syndrome and mimics.

Behçet's syndrome (BS) presents in childhood in up to 20% of reported cases. Diagnosis is clinical and multiple classification criteria have been developed. Presentation is heterogenous with recurrent oral ulceration often being the presenting feature. Mucocutaneous disease including genital ulceration and skin involvement is a common phenotype. Vascular and neurological manifestations are rarer, particularly in childhood. Musculoskeletal and gastro-intestinal involvement which do not form part of commonly used classification criteria, appear more frequent in children. Treatment approaches are extrapolated from studies of adult onset disease. The pathogenesis of BS is not well defined although dysregulation in both innate and adaptive immune systems, together with abnormal antigen presentation have been described. The recent discovery of monogenic mimics of BS requires further genetic studies to understand the burden of monogenic autoinflammatory conditions affecting those with a BS phenotype.

Development of minimum standards of care for juvenile localized scleroderma.

Juvenile localized scleroderma (jLS), also known as morphea, is an orphan disease. Pediatric guidelines regarding diagnosis, assessment, and management are lacking.Our objective was to develop minimum standards of care for diagnosis, assessment, and management of jLS. A systematic review was undertaken to establish the pediatric evidence for assessment and monitoring of jLS. An expert panel, including members of the Pediatric Rheumatology European Society (PRES) Scleroderma Working Group, were invited to a consensus meeting where recommendations were developed based on evidence graded by the systematic review and, where evidence was lacking, consensus opinion. A nominal technique was used where 75% consensus was taken as agreement. Recommendations for diagnosis, assessment, and management were developed. Due to a lack of pediatric evidence, these were primarily consensus driven. Careful assessment for extra-cutaneous manifestations including synovitis, brain involvement, and uveitis were key features together with joint assessments between Dermatology and Rheumatology to improve and standardize care. CONCLUSION: Management of jLS is varied. These recommendations should help provide standardization of assessment and care for those with this rare and potentially debilitating condition. What is Known: • Children with juvenile localized scleroderma (jLS) are managed by a number of specialties including pediatric rheumatologists and dermatologists, sometimes in shared clinics. Studies have shown that management varies considerably and that there are notable differences between specialties [1]. • There is very little published guidance on management of jLS. What is new: • These recommendations aim to standardize diagnosis, assessment, and management through review of pediatric evidence and consensus agreement. • Joint review of patients by both pediatric rheumatologists and dermatologists is recommended.

Raynaud's syndrome in children: systematic review and development of recommendations for assessment and monitoring.

OBJECTIVES: To develop recommendations for investigation and monitoring of children with Raynaud's syndrome, based on paediatric evidence collated by a systematic review. METHODS: A systematic review was undertaken to establish the paediatric evidence for assessment and monitoring of Raynaud's syndrome. An expert panel including members of the Paediatric Rheumatology European Society (PRES) Scleroderma Working Group, were invited to a consensus meeting where recommendations were developed based on evidence graded by the systematic review and where evidence was lacking, consensus opinion. A nominal technique was used where 75% consensus was taken as agreement. RESULTS: The expert panel recommended testing anti-nuclear antibody (ANA), more specific antibodies associated with connective tissue disease and nail-fold capillaroscopy in all children presenting with Raynaud's syndrome as data suggests these can be risk factors for evolution into a connective tissue disease. The frequency of follow-up recommended depends on presence of these risk factors with the aim to detect evolving connective tissue disease early in high risk individuals. Those with no abnormalities on capillaroscopy and negative autoantibodies were deemed low risk of progression, whereas those with ANA positivity, specific autoantibodies and/or nailfold capillary changes were deemed high risk and more frequent follow-up was recommended. CONCLUSIONS: Recommendations, primarily based on consensus opinion, were agreed regarding investigation and monitoring of children who present with Raynaud's syndrome. Further prospective studies are needed to better define the risk factors for progression to connective tissue disease.

United Kingdom survey of current management of juvenile localized scleroderma.

OBJECTIVES: Juvenile localized scleroderma (JLS) is a rare condition that is often difficult to assess and for which a variety of monitoring tools have been described. We aimed to describe how monitoring tools are used and perceived by clinicians in the UK, to ascertain treatments used for JLS and to provide a description of transition arrangements to adult care. METHODS: An e-survey of UK paediatric rheumatologists and dermatologists managing children and young people (CYP) with JLS was distributed using the national organisations representing these clinician groups. We asked respondents for their views and experience using 15 JLS monitoring tools, about transition services and about treatments used. RESULTS: Thirty-five dermatologists and 13 paediatric rheumatologists responded. Paediatric rheumatologists managed more CYP with JLS than dermatologists (median 16-20 and 3, respectively). Transition arrangements were reported by 43% of dermatologists and 91% of paediatric rheumatologists. Medical photography was the most frequently regularly used monitoring tool (73% respondents). The modified Rodnan skin score was the skin score used most commonly: 33% of paediatric rheumatologists and 3% of dermatologists reported using this tool frequently. Topical treatments and ultraviolet light were used by 49-80% of dermatologists and 0-8% paediatric rheumatologists. Biologic drugs and CYC were used by 0-3% of dermatologists and 31-46% of paediatric rheumatologists. CONCLUSION: How monitoring tools are accessed, used and perceived by paediatric rheumatologists and dermatologists in the UK varies between and within clinician groups, as do treatment prescribing patterns and transition arrangements. These differences will impact on the feasibility of conducting multicentre clinical trials and on standardising clinical care.

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.

Challenges and complications in juvenile localized scleroderma: A practical approach.

Juvenile localized scleroderma is characterised by inflammation which drives fibrosis in skin and soft tissues. The more severe subtypes of localized scleroderma such as linear and craniofacial are more common in children. Additionally, extracutaneous involvement is seen in half of all children and is associated with poorer treatment outcomes and health-related quality of life. Evidence for the management of craniofacial and extracutaneous involvement is lacking and therefore poses a challenge to clinicians. This review aims to provide a practical approach to management of these most challenging features of juvenile localized scleroderma through case studies where we present the available evidence, current recommendations and considerations for management.

Best clinical practice in the treatment of juvenile systemic sclerosis: expert panel guidance - the result of the International Hamburg Consensus Meeting December 2022.

INTRODUCTION: Juvenile systemic sclerosis (jSSc) is an orphan disease with a prevalence of 3 in 1,000,000 children. Currently there is only one consensus treatment guideline concerning skin, pulmonary and vascular involvement for jSSc, the jSSc SHARE (Single Hub and Access point for pediatric Rheumatology in Europe) initiative, which was based on data procured up to 2014. Therefore, an update of these guidelines, with a more recent literature and expert experience, and extension of the guidance to more aspects of the disease is needed. AREAS COVERED: Treatment options were reviewed, and opinions were provided for most facets of jSSc including general management, some of which differs from adult systemic sclerosis, such as the use of corticosteroids, and specific organ involvement, such as skin, musculoskeletal, pulmonary, and gastroenterology. EXPERT OPINION: We are suggesting the treat to target strategy to treat early to prevent cumulative disease damage in jSSc. Conclusions are derived from both expert opinion and available literature, which is mostly based on adult systemic sclerosis (aSSc), given shared pathophysiology, extrapolation of results from aSSc studies was judged reasonable.

A case series on recurrent and persisting IgA vasculitis (Henoch Schonlein purpura) in children.

BACKGROUND: IgA vasculitis (IgAV) is a small vessel vasculitis that is more common in childhood. Very limited evidence exists on patients who experience an atypical disease course. The aim of this study was to describe a cohort of children diagnosed with recurrent or persisting IgAV to identify any themes associated with their disease course and areas of unmet needs. METHODS: A single centre retrospective study of children diagnosed with recurrent or persisting IgAV at Alder Hey Children's Hospital (Liverpool, UK). Clinical data, including features at presentation and during follow up, potential triggers, abnormal laboratory and histology results, treatment and outcome at last clinical review were retrospectively collected. Key themes were identified. RESULTS: A total of 13 children met the inclusion criteria (recurrent disease, n = 4; persisting disease, n = 9). Median age at first presentation was 10.2 years [2.6-15.5], female:male ratio 1.2:1. Children in the atypical cohort were significantly older than a larger cohort of children who followed a non-complicated disease course (median age 5.5 years (range [0.6-16.7], p = 0.003)). All children re-presented with a purpuric rash (either recurring or persisting), accompanied by joint involvement in 92% of patients (12/13). Disease-modifying anti-rheumatic drugs (DMARDs) were used in 8/13 (62%) children. The median time from first presentation to diagnosis of atypical disease was 18.4 months [5.3-150.8] and the time from first presentation to treatment was 24.1 months [1.8-95.4]. Use of corticosteroids was significantly higher in children with renal involvement (p = 0.026). During follow up, 8/13 (62%) children were admitted at least once, whilst 10/13 (77%) had re-presented at least once to the emergency department. Five (38%) children were referred to psychology services and 7 (54%) children reported feelings of frustration. CONCLUSIONS: This series describes some characteristics of a small cohort of children with atypical IgAV. It also identifies unmet needs in children with atypical IgAV, which includes delays in diagnosis and lengthy waits for treatment, lack of high-quality evidence regarding treatment choices and a high unrecognised disease burden. Further research is needed to study this subgroup of children as evidence is lacking.

Demographic, clinical and laboratory differences between paediatric acute COVID-19 and PIMS-TS-results from a single centre study in the UK.

Background: Paediatric symptomatic SARS-CoV-2 infections associate with two presentations, acute COVID-19 and paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS). Phenotypic comparisons, and reports on predictive markers for disease courses are sparse and preliminary. Methods: A chart review of COVID-19 and PIMS-TS patients (≤19 years) admitted to Alder Hey Children's NHS Foundation Trust, a tertiary centre in the North-West of England, was performed (02/2020-09/2022). Results: A total of 161 symptomatic COVID-19 and 50 PIMS-TS patients were included. Peaks in admissions of patients with PIMS-TS occurred approximately 4 weeks after those for acute COVID-19. The incidence of in-patients with PIMS-TS reduced over time, and there were no admissions after February 2022. When compared to acute COVID-19, PIMS-TS patients were older (median: 10.3 years vs. 2.03 years; p < 0.001). There were no differences in gender distribution, but minority ethnicities were over-represented among PIMS-TS patients. Regional ethnic distribution was reflected among acute COVID-19 patients (66% vs. 84.5% White Caucasian, p = 0.01). Pre-existing comorbidities were more common among acute COVID-19 patients (54.7% vs. 8%, p < 0.001). PIMS-TS patients more commonly presented with abdominal symptoms (92% vs. 50.3%), neurological symptoms (28% vs. 10.6%) and skin rashes (72% vs. 16.8%), (p ≤ 0.01) when compared with acute COVID-19, where respiratory symptoms were more common (51.6% vs. 32%, p = 0.016). PIMS-TS more frequently required intensive care admission (64% vs. 16.8%), and inotropic support (64% vs. 9.3%) (all p < 0.05). More deaths occurred among acute COVID-19 patients [0 vs. 7 (4.4%)], with 5/7 (71%) in the context of pre-existing comorbidities. When compared to acute COVID-19, PIMS-TS patients exhibited more lymphopenia and thrombocytopenia, a more pronounced acute phase reaction, and more hyponatraemia (p < 0.05). Partial least square discriminant analysis of routine laboratory parameters allowed (incomplete) separation of patients at diagnosis, and variable importance projection (VIP) scoring revealed elevated CRP and low platelets as the most discriminatory parameters. Conclusion: Admissions for PIMS-TS reduced with increasing seroconversion rates in the region. Young age and pre-existing comorbidities associate with hospital admission for acute COVID-19. While PIMS-TS may present more acutely with increased need for intensive care, acute COVID-19 had an increased risk of mortality in this cohort.

Research priority setting for paediatric rheumatology in the UK.

The evidence base that underlies the management of children and young people with paediatric rheumatic diseases is deficient. In this field, there are many crucial unanswered questions. The UK Paediatric Rheumatology Clinical Studies Group, supported by UK National Institute for Health Research Clinical Research Network: children and Versus Arthritis, elicited ideas for research priorities from paediatric rheumatologists, trainees, allied health-care professionals, nurse specialists, patients, parents of patients, carers, and charities. These ideas were collected through online surveys and face-to-face meetings. A modified Delphi process was used, which included online research priority ranking surveys and a consensus workshop. A longlist of 55 disease-specific research priorities and 37 general research priorities were voted on in the first survey. A list of 11 top general research priorities was produced. The top ten disease-specific research priorities were discussed in depth at a Delphi workshop to determine their final ranking. This Health Policy paper will help to guide clinicians, academics, and funding bodies to prioritise research in paediatric rheumatic diseases, specifically in areas of unmet patient needs.

Successful integration of an automated patient-reported outcome measure within a hospital electronic patient record.

Objectives: The objective of this evaluation was to assess the feasibility of implementing a fully integrated, automated, electronic patient-reported outcome measures (ePROM) system into a hospital electronic patient record (EPR; hospital-based clinical record). Additional objectives included evaluating the effect of the system on patient-reported outcome measures (PROM) completion rates and investigating the acceptability of the ePROM. Methods: The evaluation was conducted in a rheumatology clinic in a specialist children's hospital in the UK. Paper-based childhood HAQ PROMs were already used in the clinic, and an EPR was the main hospital information system. The technical feasibility of introducing the ePROM technology was assessed using a case study approach; the effect of the system on PROM completion rates was investigated using a before-after design; and acceptability was assessed using semi-structured questionnaires and a focus group. Results: An automated and integrated ePROM system was implemented successfully in April 2021. After implementation, ∼500 automated SMS text messaging invitations to complete ePROMs were sent to care-givers each month. PROM completion rates increased from 33 of 100 (33%) to 47 of 65 (72%) after the introduction of the ePROM system (χ2 = 11.51; P < 0.05). The ePROM system was highly acceptable to patients and clinical staff. Some clinical staff expressed a concern that an electronic system might represent a barrier to care for families with more limited resources. Conclusion: High levels of automation and integration with existing technology systems seemed to be key contextual factors associated with the successful implementation and adoption of the ePROM intervention in a paediatric rheumatology clinic.