Objectives Sjögren's Syndrome (SS) with childhood onset is a rare autoimmune disease characterised by heterogeneous presentation. The lack of validated classification criteria makes it challenging to diagnose. Evidence-based guidelines for treatment of juvenile SS are not available due to the rarity of disease and the paucity of research in this patient population. This systematic review aims to summarise and appraise the current literature focused on pharmacological strategies for management of SS with childhood onset. Methods PubMed and MEDLINE/Scopus databases up to December 2020 have been screened for suitable reports highlighting pharmacological treatment of SS with childhood onset using the PRISMA 2009 reporting checklist. Animal studies have been excluded. Results 43 studies (34 case reports, 8 mini case series and one pilot study) were eligible for analysis. The studies retrieved included girls in 88% (120/137) of cases and had very low confidence level. Hydroxychloroquine (HCQ) was prescribed for parotid swelling, as well as in association with methotrexate (MTX) and non-steroidal anti-inflammatory drugs (NSAIDS) in patients with arthritis and arthralgia. Corticosteroids such as long courses of oral prednisone and IV methylprednisolone were commonly prescribed for children with severe disease presentations. Rituximab was mainly indicated for MALT lymphoma, and renal and nervous system complications. Other conventional DMARDs were prescribed in selected cases with extra-glandular manifestations. Conclusion Various therapies are used for the management of juvenile SS and are prescribed based on expert clinician’s opinion. There are currently no good quality studies that allow clinical recommendations for treatment in SS with childhood onset.

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Introduction/Background Embedding research into clinical practice has many benefits, with research-active healthcare settings reporting better clinical outcomes and improved staff recruitment and retention. This is recognised by the NHS who aim to ‘build the capacity and capability of our current and future workforce to embrace and actively engage with research’. In spite of this, clinical academic capacity across the NHS remains challenging; the number of consultants working in clinical academia has declined in recent years and there is concern about lack of academic progression for non-medical professions. Reported barriers include clinical pressures and lack of dedicated time, individual skill and confidence. Description/Method Our aim was to gather information about research exposure across the Paediatric Rheumatology multidisciplinary team (MDT), including paediatric trainees (rheumatology grid, rheumatology spin and level 2 trainees), clinical nurse specialists (CNS), advanced nurse practitioners (ANPs) and Allied Health Professionals (AHPs). We initially sought to identify if trainees were receiving adequate research opportunities during their training. A pilot questionnaire was distributed, and results collated and presented at the Spring Clinical Studies Group (CSG) annual meeting. Feedback was received from both questionnaire respondents and the CSG. Following this, we modified and broadened the scope of the questionnaire to include the Paediatric Rheumatology MDT, with the aim of comparing experiences across the MDT. This was developed using an online survey platform with the link distributed via email and messaging groups for trainees, AHPs and CNSs. The aims of the modified questionnaire were to; 1. Understand the current research experience across the paediatric rheumatology MDT and identify barriers and ways to support participation in research. 2. Identify if individuals wanted more exposure to research and what specific research skills they would like to develop. Discussion/Results There were 34 respondents: 14 (41%) paediatric trainees (7 grid, 2 spin, 2 post-CCT fellows, 3 level-2 trainees), 14 (41%) CNS, 4 (12%) AHPs and 2(6%) ANPs. Across the MDT, 19 respondents (56%) agreed they had adequate opportunity to be involved in research, of which 7 (21%) strongly agreed. In terms of research exposure, 22 (65%) have undertaken postgraduate degrees, 5 (15%) PhD, 9 (26%) MSc, 5 (15%) diploma and 6 (18%) postgraduate certificate. Eight-respondents (24%) had taken time out to develop research skills. Research experience:  18 respondents (53%) have been on the delegation-log for clinical trials. 20 (59%) have contributed to data collection for National Registries. 23 (68%) have given a poster/oral presentation at national/international conferences and 15 (44%) have published in peer-reviewed journals - the majority trainees (n = 11,73%). Research training:  51% report adequate training in critical appraisal, 48% in literature review and 40% in consent; fewer reported adequate training in designing research projects (21%), ethics applications (21%) and statistical analysis (23%). Further training would be desirable in: • designing research projects (68%); • discussing research with patients (65%); • statistical analysis (49%); • critical appraisal (40%); • literature search (37%). Future research involvement:  94% would like more opportunities to be involved in research. In the future, 63% would like allocated research time, 6% to be mainly academic (1 CNS, 1 trainee) and 12% to be full-time clinical (1 spin, 1 level-2 trainee, 2 CNS). Barriers to research:  Free text answers were used to gather information and common themes identified included lack of: • time/heavy clinical commitment (60%); • supervision/support from seniors (9%); • local resources (9%); • research funding (9%); • awareness of projects (12%); • research skills (9%). Encourage participation in research:  Common suggestions included: • protected research time during training/career (35%); • further research training (21%); • earlier awareness of projects/trials (18%); • Increased support from more experienced colleagues (15%); • improved collaboration/networking (12%). Key learning points/Conclusion This survey provides an interesting insight into the research experience throughout the Paediatric Rheumatology MDT. It is encouraging that within the Rheumatology MDT 56% of respondents reported that they have had adequate opportunities to be involved in research and the majority have presented or published their research. However, 94% have reported they would like more opportunities to be involved in research. Lack of time was reported as the most common barrier to research involvement; this finding is consistent with the British Society for Rheumatology’s 2019 ‘Paediatric State of Play’ report. Additionally, significant numbers report they would like further training in research skills. Academic writing for publication was noted as a particular area of concern for nurses and AHPs. We advocate for further research opportunities throughout the MDT. For Rheumatology trainees, it was suggested that research skills be incorporated into the curriculum, with dedicated time allocated to gain experience and contribute to research. All members of the MDT may benefit from research skills training courses, although this would need to be carefully considered, given lack of time and resources were common barriers reported by respondents. Several professionals reported lack of support or supervision from seniors and suggested the benefit of mentoring networks. A weakness of this study is the relatively low number of respondents; the survey remains open and we intend to collect further data to maximise representation across the MDT. Additionally, there is potential bias, with individuals with a research interest possibly more likely to contribute, meaning research experience may be over-represented by this sample of the MDT. Also, representation from AHPs was limited compared to paediatric trainees and CNS. Further work is needed to understand research experience across the MDT, however this initial survey is a valuable first step in encouraging discussion of MDT participation in research.

Introduction/Background MAS is a severe, potentially fatal complication of systemic JIA (sJIA). It is characterised by uncontrolled activation and proliferation of T cells and macrophages, leading to a “cytokine storm” which manifests as hyperinflammation. Its consequences include fever, rash, cytopenias, transaminitis, coagulopathy and hyperferritinaemia. Prompt careful assessment is required to identify MAS and exclude other conditions like sepsis. This is often done in parallel, performing a septic screen and commencing antibiotics whilst considering immunosuppressive therapy and its timing. MAS can be refractory to familiar first line agents, presenting a challenge for Paediatric Rheumatologists as no consensus guidelines exist to inform management. Description/Method We present a case of a 15-month-old girl with sJIA and refractory MAS. Our patient became unwell at 8-months of age with fever and rash. She was initially treated with antibiotics. She then developed peeling of the fingers and toes. Management of Kawasaki Disease was initiated - IVIG (2 doses), IV methylprednisolone (IVMP) for 5 days, followed by oral prednisolone for ten days, and aspirin. Her fever persisted. The prednisolone and aspirin doses were increased which resulted in clinical improvement. After a few weeks, the fever recurred three times daily and associated with an erythematous rash. She was admitted to hospital and treated with antibiotics for a presumed UTI. The diagnosis of sJIA was made after exclusion of other infectious and haematological causes. Despite IVMP followed by oral prednisolone and anakinra, the fever persisted. She was transferred to our hospital for further management. Initial bloods showed Hb 103g/L, platelets 257x109/L, WBC 13.07x109/L, Neutrophils 4.18x109/L, ESR 32mm/hr, CRP 30mg/L, ferritin 2201ng/mL, ALT 89U/L, AST 218U/L, LDH 1859IU/L, triglycerides 4.2mmol/L, fibrinogen 2.8mg/dL, d-dimers 4641ng/mL. She was pulsed with IVMP for 3 days. The anakinra dose increased. Remission was not achieved biochemically. A further pulse with IVMP (3 days) was given with no improvement. IV ciclosporin was added. Tocilizumab 12mg/kg/day once daily was commenced. She remained on oral prednisolone 2mg/kg/day. She then developed sepsis. She had a positive blood culture from her PICC line. Despite IV antibiotics, her clinical picture didn’t improve. She eventually developed septic shock requiring a fluid bolus and worsening MAS. The PICC line was removed. She also required amlodipine for hypertension. There was no sign of MAS remission (table 1), and the decision was made to commence etoposide (initial 150mg/M2 for 6 doses; current dose 50mg/M2) whilst working our patient up for a HSCT eight months after first presentation. Discussion/Results MAS is a severe complication of sJIA. MAS can progress very rapidly and if left untreated, it is associated with high morbidity and mortality. Abnormal investigations include cytopenia, coagulopathy and hyperferritinaemia. These distinctive features usually occur in the later stages of MAS. This can lead to a delay in the diagnosis of the condition, resulting in a worse outcome. Early recognition of MAS is key to improving morbidity and mortality. The mainstay of treatment for MAS is glucocorticoids. However, as this patient highlights glucocorticoids alone are not often satisfactory in controlling the disease. Other treatments can be used, but there is a paucity of data from clinical trials as to what treatment should be used and in what order. HSCT is a potentially curative option for patients with refractory sJIA. Some of these patients can achieve drug free remission, although not all. In some, disease remission is only transient. HSCT is associated with significant risks, in particular Graft versus Host Disease. The data on success of HSCT in sJIA is sparce – making it challenging for clinicians to counsel parents. Currently this patient’s condition is being controlled with Etoposide whilst HSCT is awaited. Etoposide is a well-established therapy for Primary Hemophagocytic Lymphhistiocytosis (HLH). As clinicians we are continuing to learn more about its use in controlling sJIA. A recent article by Horne et al suggests that a moderate dose of etoposide may be beneficial in severe/refractory HLH. We are currently trialling this approach in our patient with the hope of decreasing the overall Etoposide dose, aiming to minimise toxicity whilst adequately controlling her disease. Finally, it is vital to screen for primary HLH in those whose first rheumatological presentation is with MAS. An important differential is a genetic cause which may or may not be identifiable. Key learning points/Conclusion Learning points: Improved awareness of MAS is paramount to aid timely diagnosis and ensure prompt treatment in order to try and improve MAS associated morbidity and mortality. Careful evaluation of serum ferritin in conjunction with other blood parameters is important and helpful in monitoring response to therapy. It is vital to screen for Primary HLH in patients whose first rheumatological presentation is MAS. There is a lack of evidence for treatment pathways in refractory sJIA and MAS. Some children develop refractory MAS and HSCT needs to be seriously considered, but when should clinicians consider HSCT? Many unanswered questions exist. It can be challenging as clinicians to know when to refer patients for HSCT and how best to manage these patients whilst awaiting HSCT. It would be useful to develop consensus guidelines to help answer some of the following questions: When should a child be referred for HSCT? How many drugs should be trialled prior to referral? What is the definition of treatment failure? Who should decide that the child should be referred for HSCT? What treatment should be used to bridge to HSCT and at what dose?

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