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Background: The active involvement of patients and the public in the design and delivery of health research has been increasingly encouraged, if not enforced. Knowledge of how this is realised in practice, especially where children and young people (CYP) are concerned, is limited, partly due to the low level of reporting of patient and public involvement (PPI) in general. The aim of this work was to assess how researchers funded by the National Institute for Health and Care Research (NIHR) report the involvement of CYP in the design and conduct of child health research to better understand the opportunities offered to CYP, and the realities of involvement in practice., Methods: A participation matrix, analysis framework and accompanying tools were adapted from existing frameworks, including a child-rights informed framework, the Guidance for Reporting Involvement of Patients and the Public Checklist Short Form (GRIPP2SF), and NIHR reporting expectations. Child-focused research reports were identified from the NIHR Journals Library, including any interventional or observational study involving CYP aged 0-< 24 years. In two co-design workshops with healthcare professionals and CYP, we tested and refined the participation matrix, analysis framework and accompanying tools., Results: Only thirty-two NIHR reports out of 169 (19%) were identified as relevant and included reporting of PPI with CYP. We identified significant variability in the way PPI with CYP was reported. Only 4/32 (12%) reports fully met NIHR (and GRIPP2SF) reporting criteria. Only 3/32 (9%) reports formally evaluated or self-reflected on PPI activities with CYP, whilst 15/32 (47%) provided minimal information about CYP involvement. The most common approach to involving CYP (23/32, 72%) was through the medium of existing groups or networks., Conclusion: Despite the NIHR's commitment to increase the quality, transparency, and consistency of reporting PPI, the reporting of involvement with CYP remains sub-optimal. Neglecting to report key details of involvement methods and impacts deprives the research community of knowledge to advance the field of delivering 'meaningful' PPI with CYP. Practical guidance on how researchers can report the processes and outputs of CYP involvement more rigorously may help child health researchers to involve them more meaningfully. This research offers practical tools informed by CYP to aid the reporting process., (© 2023. The Author(s).)

Juvenile idiopathic arthritis (JIA) is the most common paediatric rheumatological disorder and is classified by subtype according to International League of Associations for Rheumatology criteria. Depending on the number of joints affected, presence of extra-articular manifestations, systemic symptoms, serology and genetic factors, JIA is divided into oligoarticular, polyarticular, systemic, psoriatic, enthesitis-related and undifferentiated arthritis. This review provides an overview of advances in understanding of JIA pathogenesis focusing on aetiology, histopathology, immunological changes associated with disease activity, and best treatment options. Greater understanding of JIA as a collective of complex inflammatory diseases is discussed within the context of therapeutic interventions, including traditional non-biologic and up-to-date biologic disease-modifying anti-rheumatic drugs. Whilst the advent of advanced therapeutics has improved clinical outcomes, a considerable number of patients remain unresponsive to treatment, emphasising the need for further understanding of disease progression and remission to support stratification of patients to treatment pathways., (© 2021. The Author(s).)

Background: Lupus nephritis (LN) is a severe consequence of systemic lupus erythematosus (SLE) that affects approximately 40% of patients. Pathogenic immune complexes that are characteristic of LN deposit in the kidney and activate immune mediated pathways including the complement system. Complete remission rates in LN are approximately 44% highlighting the need for new treatment strategies in these patients. Eculizumab is a fully humanised IgG2/IgG4 monoclonal antibody directed at C5 and thus prevents the formation of the terminal complement complex. Eculizumab is successfully used in atypical haemolytic uraemic syndrome (aHUS) and paroxysomal nocturnal haemoglobinuria (PNH) but it is not standardly used in LN. The aim of this project was to determine whether there is any role for eculizumab as adjunctive therapy in LN., Methods: Using a predefined search strategy on Ovid MEDLINE and EMBASE the literature was reviewed systematically to identify studies in which eculizumab had been used to treat patients with SLE. All patients were included that were treated with complement inhibitors. Favourable outcome in this study was defined as resolution of symptoms that led to treatment, discharge from hospital or recovery of renal function. Patients were excluded if there was no outcome data or if complement inhibition was unrelated to their SLE., Results: From 192 abstracts screened, 14 articles were identified, involving 30 patients. All SLE patients administered eculizumab were treated for thrombotic microangiopathy (TMA) secondary to LN diagnosed either histologically (66%) or as part of a diagnosis of aHUS (73%). 93% of patients had a favourable outcome in response to eculizumab treatment, of which 46% had a favourable outcome and successfully stopped treatment without relapse in symptoms during a median follow up of 7 months. Three patients (10%) reported adverse outcomes related to eculizumab therapy., Conclusions: Scientific evidence supports the involvement of complement in the pathogenesis of LN however the role of complement inhibition in clinical practice is limited to those with TMA features. This systematic review showed that in cases of LN complicated with TMA, eculizumab seems to be a very efficacious therapy. Further evidence is required to determine whether patients with refractory LN may benefit from adjunctive complement inhibition.

Background: Lupus nephritis (LN) affects up to 80% of juvenile-onset systemic lupus erythematosus patients. Mesangial cells (MCs) comprise a third of the glomerular cells and are key contributors to fibrotic changes within the kidney. This project aims to identify the roles of MCs in an in vitro model of LN., Methods: Conditionally immortalised MCs were treated with pro-inflammatory cytokines or with patient sera in an in vitro model of LN and assessed for their roles in inflammation and fibrosis., Results: MCs were shown to produce pro-inflammatory cytokines in response to a model of the inflammatory environment in LN. Further the cells expressed increased levels of mRNA for extracellular matrix (ECM) proteins ( COL1A1, COL1A2, COL4A1 and LAMB1 ), matrix metalloproteinase enzymes ( MMP9 ) and tissue inhibitors of matrix metalloproteinases ( TIMP1 ). Treatment of MCs with serum from patients with active LN was able to induce a similar, albeit milder phenotype. Treatment of MCs with cytokines or patient sera was able to induce secretion of TGF-β1, a known inducer of fibrotic changes. Inhibition of TGF-β1 actions through SB-431542 (an activin A receptor type II-like kinase (ALK5) inhibitor) was able to reduce these responses suggesting that the release of TGF-β1 plays a role in these changes., Conclusions: MCs contribute to the inflammatory environment in LN by producing cytokines involved in leukocyte recruitment, activation and maturation. Further the cells remodel the ECM via protein deposition and enzymatic degradation. This occurs through the actions of TGF-β1 on its receptor, ALK5. This may represent a potential therapeutic target for treatment of LN-associated fibrosis., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s). 2019.)

Background: Patient recruitment can be very challenging in paediatric studies, especially in relatively uncommon conditions, such as juvenile idiopathic arthritis (JIA). However, involving children and young people (CYP) in the design of such trials could promise a more rapid trajectory towards making evidence-based treatments available. Studies involving CYP are advocated in the literature but we are not aware of any early stage feasibility studies that have qualitatively accessed the perspectives of parents and CYP with a long term condition to inform design and conduct of a trial. In the context of a feasibility study to inform the design of a proposed randomised controlled trial of corticosteroid induction regimen in JIA, we explored families' perspectives on the proposed trial and on JIA trials generally., Methods: We analysed interviews with 27 participants (8 CYP aged 8-16 years and 19 parents) from four UK paediatric rheumatology centres. CYP had recently received corticosteroids to treat JIA. Audio-recorded interviews were transcribed and analysed thematically, drawing on the Framework Method., Results: Both parents and CYP were capable of engaging with the logic of the proposed trial but pointed to challenges with its design. Treatment preferences influenced willingness to participate in the proposed trial. The preferences of older children and their parents often differed, with CYP being more willing to participate in the proposed trial than parents. Families' current treatment preferences were largely informed by past positive and negative treatment experiences. Some participants also indicated that their treatment preferences were influenced by those of their clinicians., Conclusion: Previous research has typically focused on deficits in patients' understandings of trials. We found that both parents and CYP understood trial concepts and were able to identify potential flaws in the proposed trial. We propose recommendations to optimise the design of a planned corticosteroid induction regimen trial in JIA. Accessing both parents' and CYP's perspectives helps to identify and address recruitment challenges, which will ultimately optimise informed consent and future recruitment.

Background: Proteinuria is a well-known risk factor for progression of renal dysfunction in a variety of chronic kidney diseases. In adult-onset Systemic Lupus Erytematosus (SLE) patients with lupus nephritis (LN), proteinuria takes a significant period of time to normalise, with proteinuric remission being associated with improved renal survival and reductions in mortality. The length of time required to attain proteinuric remission has not previously been investigated in Juvenile-onset SLE (JSLE). The aim of this study was to elucidate when proteinuric remission occurs, and whether clinical/demographic factors at LN onset bear influence on the time to proteinuric remission., Methods: Participants of the UK JSLE Cohort Study and Repository were included if they had active LN (renal biopsy and/or renal British Isles Lupus Assessment Grade (BILAG) score defined active LN) and proteinuria. Univariate Cox proportional hazard regression modelling was used to explore factors associated with time to proteinuric recovery. Covariates with p-value < 0.2 were included in a multivariable Cox regression model, and backward stepwise variable selection applied., Result: 64/350 (18%) of UK JSLE Cohort Study patients fulfilled the study inclusion criteria. 25 (39%) achieved proteinuric remission within a median of 17 months (min 2.4, max 78). Within a multivariate Cox proportional hazard regression model, age at time of LN flare (p = 0.007, HR 1.384, CI 1.095-1.750), eGFR (p = 0.035, HR 1.016, CI 1.001-1.030) and haematological involvement (p = 0.016, HR 0.324, CI 0.129-0.812) at the time of LN onset were found to be significantly associated with time to proteinuric recovery., Conclusions: A significant proportion of children with LN have on-going proteinuria approximately two years after their initial flare. Poor prognostic factors all at time of LN onset include younger age, low eGFR, and concomitant haematological involvement.

Introduction: Methotrexate (MTX) is a cornerstone of treatment in a wide variety of inflammatory conditions, including juvenile idiopathic arthritis (JIA) and juvenile dermatomyositis (JDM). However, owing to its narrow therapeutic index and the considerable interpatient variability in clinical response, monitoring of adherence to MTX is important. The present study demonstrates the feasibility of using methotrexate polyglutamates (MTXPGs) as a biomarker to measure adherence to MTX treatment in children with JIA and JDM., Methods: Data were collected prospectively from a cohort of 48 children (median age 11.5 years) who received oral or subcutaneous (SC) MTX therapy for JIA or JDM. Dried blood spot samples were obtained from children by finger pick at the clinic or via self- or parent-led sampling at home, and they were analysed to determine the variability in MTXPG concentrations and assess adherence to MTX therapy., Results: Wide fluctuations in MTXPG total concentrations (>2.0-fold variations) were found in 17 patients receiving stable weekly doses of MTX, which is indicative of nonadherence or partial adherence to MTX therapy. Age (P = 0.026) and route of administration (P = 0.005) were the most important predictors of nonadherence to MTX treatment. In addition, the study showed that MTX dose and route of administration were significantly associated with variations in the distribution of MTXPG subtypes. Higher doses and SC administration of MTX produced higher levels of total MTXPGs and selective accumulation of longer-chain MTXPGs (P < 0.001 and P < 0.0001, respectively)., Conclusions: Nonadherence to MTX therapy is a significant problem in children with JIA and JDM. The present study suggests that patients with inadequate adherence and/or intolerance to oral MTX may benefit from SC administration of the drug. The clinical utility of MTXPG levels to monitor and optimise adherence to MTX in children has been demonstrated., Trial Registration: ISRCTN Registry identifier: ISRCTN93945409 . Registered 2 December 2011.

Background: Juvenile dermatomyositis (JDM) is a rare autoimmune inflammatory disorder associated with significant morbidity and mortality. International collaboration is necessary to better understand the pathogenesis of the disease, response to treatment and long-term outcome. To aid international collaboration, it is essential to have a core set of data that all researchers and clinicians collect in a standardised way for clinical purposes and for research. This should include demographic details, diagnostic data and measures of disease activity, investigations and treatment. Variables in existing clinical registries have been compared to produce a provisional data set for JDM. We now aim to develop this into a consensus-approved minimum core dataset, tested in a wider setting, with the objective of achieving international agreement., Methods/design: A two-stage bespoke Delphi-process will engage the opinion of a large number of key stakeholders through Email distribution via established international paediatric rheumatology and myositis organisations. This, together with a formalised patient/parent participation process will help inform a consensus meeting of international experts that will utilise a nominal group technique (NGT). The resulting proposed minimal dataset will be tested for feasibility within existing database infrastructures. The developed minimal dataset will be sent to all internationally representative collaborators for final comment. The participants of the expert consensus group will be asked to draw together these comments, ratify and 'sign off' the final minimal dataset., Discussion: An internationally agreed minimal dataset has the potential to significantly enhance collaboration, allow effective communication between groups, provide a minimal standard of care and enable analysis of the largest possible number of JDM patients to provide a greater understanding of this disease. The final approved minimum core dataset could be rapidly incorporated into national and international collaborative efforts, including existing prospective databases, and be available for use in randomised controlled trials and for treatment/protocol comparisons in cohort studies.

Background: The TAM-receptor tyrosine kinase family, Tyro3, Axl and Mer are key to apoptotic cell clearance. Reduced phagocytic clearance in systemic lupus erythematosus (SLE) leads to prolonged exposure of nuclear autoantigen to the immune system. Here we measure the levels of TAM receptors and the phagocytic capacity of monocytes and macrophages in juvenile-onset SLE (JSLE)., Method: Mer protein was measured on monocytes from JSLE, healthy control and JIA patients. JSLE, healthy control and JIA patients' plasma were analysed for soluble Mer (sMer), soluble Tyro3 (sTyro) and soluble Axl (sAxl). A phagocytosis assay measured the effect of JSLE serum on phagocytic potential of JSLE and control monocytes to engulf E. Coli bacteria and healthy macrophages to engulf apoptotic neutrophils., Results: Mer receptor expression was significantly decreased on JSLE monocytes compared to healthy controls. Plasma sMer, sTyro and sAxl were significantly increased in JSLE patients compared to controls (p < 0.05). Adult healthy control macrophages had significantly decreased phagocytosis of E. Coli and apoptotic neutrophils in the presence of 10% JSLE serum compared to control serum (p < 0.05)., Conclusion: JSLE patients have a decreased phagocytosis due to both serum and cell-derived factors. Significantly increased levels of sMer, sTyro3 and sAxl may be important factors contributing to the deficit in phagocytosis ability.

Patients diagnosed with juvenile-onset systemic lupus erythematosus (JSLE) often have skin and oral lesions as part of their presentation. These mucocutaneous lesions, as defined by the American College of Rheumatology (ACR) in 1997, include malar rash, discoid rash, photosensitivity and oral ulcers. It is therefore essential to recognize mucocutaneous lesions to accurately diagnose JSLE. The mucocutaneous lesions can be divided into those with classical histological features (LE specific) and those strongly associated with and forming part of the diagnostic spectrum, but without the classical histological changes of lupus (LE nonspecific). A malar rash is the most commonly associated LE specific dermatological presentation. This skin manifestation is an acute form and also correlates with disease activity. Subacute (polycyclic or papulosquamous lesions) and chronic (discoid lesions) forms, whilst showing classical histological changes supportive of lupus, are less commonly associated with systemic lupus and do not correlate with disease activity. The most commonly associated skin lesions without classical lupus changes are cutaneous vasculitis, oral ulcers and diffuse non-scarring alopecia. These signs frequently relate to disease activity. An understanding of cutaneous signs and symptoms of lupus in children is important to avoid delay in diagnosis. They will often improve as lupus is adequately controlled and their reappearance is often the first indicator of a disease flare.

Background: Juvenile dermatomyositis (JDM) is a rare but severe autoimmune inflammatory myositis of childhood. International collaboration is essential in order to undertake clinical trials, understand the disease and improve long-term outcome. The aim of this study was to propose from existing collaborative initiatives a preliminary minimal dataset for JDM. This will form the basis of the future development of an international consensus-approved minimum core dataset to be used both in clinical care and inform research, allowing integration of data between centres., Methods: A working group of internationally-representative JDM experts was formed to develop a provisional minimal dataset. Clinical and laboratory variables contained within current national and international collaborative databases of patients with idiopathic inflammatory myopathies were scrutinised. Judgements were informed by published literature and a more detailed analysis of the Juvenile Dermatomyositis Cohort Biomarker Study and Repository, UK and Ireland., Results: A provisional minimal JDM dataset has been produced, with an associated glossary of definitions. The provisional minimal dataset will request information at time of patient diagnosis and during on-going prospective follow up. At time of patient diagnosis, information will be requested on patient demographics, diagnostic criteria and treatments given prior to diagnosis. During on-going prospective follow-up, variables will include the presence of active muscle or skin disease, major organ involvement or constitutional symptoms, investigations, treatment, physician global assessments and patient reported outcome measures., Conclusions: An internationally agreed minimal dataset has the potential to significantly enhance collaboration, allow effective communication between groups, provide a minimal standard of care and enable analysis of the largest possible number of JDM patients to provide a greater understanding of this disease. This preliminary dataset can now be developed into a consensus-approved minimum core dataset and tested in a wider setting with the aim of achieving international agreement.

Background: T cells are important to systemic lupus erythematosus (SLE) disease progression. This study determined the pro-inflammatory potential of T cells within the rare condition juvenile-onset SLE (JSLE)., Method: IL-17A and Th1/Th2-related cytokine concentrations were measured in plasma/serum from JSLE patients (n = 19, n = 11) and HC (n = 18, n = 7). IL17A, RORC, IL23 and IL23R mRNA were measured in peripheral blood mononuclear cells (PBMCs) from JSLE and healthy controls (HC) (n = 12). Th17-associated cytokine expression was analysed in the supernatant of CD3/CD28 activated JSLE (n = 7) and HC (n = 6) PBMCs., Results: JSLE plasma IL-17A level (21.5 ± 5.2 pg/ml) was higher compared to HC (7.2 ± 2.5 pg/ml, p = 0.028). No differences were found in Th1/Th2 cytokines levels. IL = 17A (p = 0.022), IL-6 (p = 0.028) and IL-21 (p = 0.003) concentrations were increased in supernatants from activated JSLE PBMCs. IL-17 F (p = 0.50) and IL-22 (p = 0.43) were also increased but were not statistically significant. IL17A and IL23 mRNA was significantly higher in JSLE PBMCs (p = 0.018 and p = 0.01)., Conclusion: JSLE T cells have an increased ability to secrete Th17 associated cytokines once activated, which could contribute to the pro-inflammatory disease phenotype seen in these patients.

Background: Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. Children with JIA are at risk of inflammation of the uvea in the eye (uveitis). Overall, 20% to 25% of paediatric uveitis is associated with JIA. Major risk factors for development of uveitis in JIA are oligoarticular pattern of arthritis, an age at onset of arthritis of less than seven years of age, and antinuclear antibody positivity. In the initial stages of mild to moderate inflammation the uveitis is asymptomatic. This has led to current practice of screening all children with JIA for uveitis. Approximately 12% to 38% of patients with JIA develop uveitis in seven years following onset of arthritis. In 30% to 50% of children with JIA-associated uveitis structural complications are present at diagnosis. Furthermore about 50% to 75% of those with severe uveitis will eventually develop visual impairment secondary to ocular complications such as cataract and glaucoma. Defining the severity of inflammation and structural complications in uveitis patients is now possible following Standardised Uveitis Nomenclature (SUN) guidelines, and modified to incorporate the consensus of end point and outcome criteria into the design of randomised trials. Despite current screening and therapeutic options (pre-biologics) 10% to 15% of children with JIA-associated uveitis may develop bilateral visual impairment and certified legally blind. To date, there remains no controlled trial evidence of benefits of biologic therapy., Methods/design: This study will randomise 154 patients aged 2 to 18 years with active JIA-associated uveitis (despite methotrexate (MTX) treatment for at least 12 weeks). All participants will be treated for 18 months, with follow up of 3 years from randomisation (continuing on MTX throughout). All participants will receive a stable dose of MTX and in addition either adalimumab (20 mg/0.8 ml for patients<30 kg or 40 mg/0.8 ml for patients weighing 30 kg or more, subcutaneous (s/c) injection every 2 weeks based on body weight), or placebo (0.8 ml as appropriate according to body weight) s/c injection every 2 weeks., Discussion: This is the first randomised controlled trial that will assess the clinical effectiveness, safety and cost effectiveness of adalimumab in combination with methotrexate for the treatment of juvenile idiopathic arthritis associated uveitis., Trial Registration: ISRCTN10065623.