O18 The Rollercoaster Reality of Mixed Connective Tissue disease

Abstract Case report - Introduction Childhood-onset mixed connective tissue disease (MCTD) is rare and heterogeneous presenting both diagnostic and treatment challenges. Symptoms often present sequentially over an extended period of time, requiring a high index of suspicion and careful clinical evaluation to diagnose. We present the cases of two young women which demonstrate the evolution of this disease and the diagnostic and management challenges. Summarising these two cases from childhood, through adolescence and into adult life will highlight the importance of integrated clinical pathways and effective transition in managing their disease. Case report - Case description Case 1: Twenty-year-old female presented in 2016, age 15 years with polyarthritis, Raynaud’s phenomenon, fatigue, and headaches – rheumatoid-factor (RF) positive, anti-RNP antibody positive, Smith antibody positive at diagnosis. Initially treated with methotrexate, prednisolone, and hydroxychloroquine. Due to methotrexate-associated nausea, she switched to sulfasalazine but remained steroid dependent requiring several doses of methyl prednisolone. Treatment was escalated, and transfer delayed, and in 2017 (age 16) she had rituximab with good efficacy. She transferred into adult rheumatology with careful monitoring for symptom evolution. Her arthritis flared in November 2019, associated with fatigue and malaise, and she developed immune thrombocytopenia (ITP) in April 2020. The combination of arthritis, ITP, malaise, and activation of complement (without other features of lupus) necessitated a further pulse of rituximab with resolution of symptoms and normalisation of complement. Case 2: Twenty-two-year-old female presented in 2006, age 9 with fatigue, polyarthritis, leucopoenia, and positive ANA. Managed as JIA with prednisolone, methotrexate and etanercept then switched to infliximab as features of juvenile dermatomyositis developed. Arthritis and muscle weakness worsened with Raynaud’s phenomenon developing and new sclerodactyly. Serology evolved with positive ANA, anti-RNP antibodies and positive RF leading to diagnosis of MCTD. Treatment included azathioprine and mycophenolate mofetil (MMF). Disease escalated and cyclophosphamide/rituximab administered. Remission was reached in 2011, age 13, and maintained with rituximab, methotrexate, and hydroxychloroquine. Transition into adult services was carefully planned and transfer occurred in a period of remission age 17. In adult services she is stable on azathioprine and hydroxychloroquine and sclerodactyly has completely regressed. Treatment complications are evident -panhypogammaglobulinaemia secondary to rituximab treatment and steroid induced osteoporosis/fracture. Case report - Discussion MCTD was first suggested as a distinct entity in 1972 by Sharp and colleagues. There is a lack of consensus over the four published diagnostic criteria (Kasukawa’s, Alarcon-Segovia, Kahn and Sharp), none of which have been validated for use in children. Heterogeneity of clinical features and the rarity of childhood-onset MCTD makes diagnosis a challenge. Raynaud’s phenomenon and polyarthritis are the most common presenting features. It was only with time that the clinical picture of MCTD emerged. There is limited evidence available to guide treatment but emerging evidence of benefit from rituximab. Management aims to minimise active inflammation and treatment toxicity balancing the evolving clinical picture with side effects from treatments used, as exemplified in these two cases. Given potential evolution to SLE anti-TNF drugs are usually avoided but in case 2 when this appeared phenotypically to be JIA/JDM both etanercept and infliximab were used. In Sheffield transfer usually occurs around the end of school year 11 but for case 1 this was the time of maximum clinical instability. Transition was delayed enabling treatment with rituximab in a familiar environment and transfer only occurred when disease was stable. In case 2 with such intensive treatment in paediatric rheumatology transition planning carefully emphasised the clinical features and medicines used which has been of great benefit in adult services to maintain disease control and quiescence and avoid risks of over treatment. An integrated transition pathway from paediatric to adult services has ensured a safety net to the evolving nature of these inflammatory diseases and allowed a joint approach to the diagnosis and management. Case report - Key learning points: Evolution of disease Paediatric-onset MCTD is rare. As paediatric and adolescent rheumatologists we will be seeing patients early in the disease course. We need an awareness of the potential for our inflammatory patients’ symptoms to evolve and to re-assess the diagnosis when this happens. Respect anti-RNP antibodies anti-RNP antibodies, either at disease outset (case 1) or occurring later in disease course (case 2) help distinguish evolving MCTD, presenting with polyarthritis with or without Raynaud’s phenomenon, from ‘straightforward’ polyarticular JIA. Children and young people who have anti-RNP antibodies need to be watched carefully for evolution of MCTD symptoms. Integrated Transition As MCTD may evolve over several years, a close partnership between paediatric and adult rheumatology (whether part of an integrated adolescent transition service or not) helps deliver developmentally appropriate health care. Expect complications Paediatric onset MCTD tends to have a milder disease course than in adults, although complete remission is rare. The most common causes of death are linked to pulmonary hypertension and interstitial lung disease. However, these complications are less seen in children. Clinical vigilance and proactive screening in watching for development of the disease and trying to anticipate potential problems are important. This requires multi-disciplinary team working. This is just as important when managing treatment effects such as panhypogammaglobulinaemia and liaison with immunology team or steroid side effects and liaison with endocrinology team. Individualised Approach There is no one specific treatment for MCTD. The heterogeneity of the condition dictates an individualised approach using best available evidence. It is particularly important to review treatment strategies as new symptoms emerge, or side-effects emerge from treatments being used.

Case report -Introduction: Childhood-onset mixed connective tissue disease (MCTD) is rare and heterogeneous presenting both diagnostic and treatment challenges. Symptoms often present sequentially over an extended period of time, requiring a high index of suspicion and careful clinical evaluation to diagnose. We present the cases of two young women which demonstrate the evolution of this disease and the diagnostic and management challenges. Summarising these two cases from childhood, throughadolescenceandintoadult lifewillhighlighttheimportance of integrated clinical pathways and effective transition in managing their disease. Case report -Case description: Case 1: Twenty-year-old female presented in 2016, age 15 years with polyarthritis, Raynaud's phenomenon, fatigue, and headaches -rheumatoid-factor (RF) positive, anti-RNP antibody positive, Smith antibody positive at diagnosis. Initially treated with methotrexate, prednisolone, and hydroxychloroquine. Due to methotrexate-associated nausea, she switched to sulfasalazine but remained steroid dependent requiring several doses of methyl prednisolone. Treatment was escalated, and transfer delayed, and in 2017 (age 16) she had rituximab with good efficacy. She transferred into adult rheumatology with careful monitoring for symptom evolution. Her arthritis flared in November2019, associated with fatigue and malaise, and shedeveloped immune thrombocytopenia (ITP) in April 2020. The combination of arthritis, ITP, malaise, and activation of complement (without other features of lupus) necessitated a further pulse of rituximab with resolution of symptoms and normalisation of complement. Case 2: Twenty-two-year-old female presented in 2006, age 9 with fatigue, polyarthritis, leucopoenia, and positive ANA. Managed as JIA with prednisolone, methotrexate and etanercept then switched to infliximab as features of juvenile dermatomyositis developed. Arthritis and muscle weakness worsened with Raynaud's phenomenon developing and new sclerodactyly. Serology evolved with positive ANA, anti-RNP antibodies and positive RF leading to diagnosis of MCTD. Treatment included azathioprine and mycophenolate mofetil (MMF). Disease escalated and cyclophosphamide/rituximab administered. Remission was reached in 2011, age 13, and maintained with rituximab, methotrexate, and hydroxychloroquine. Transition into adult services was carefully planned and transfer occurred in a period of remission age 17. In adult services she is stable on azathioprine and hydroxychloroquine and sclerodactyly has completely regressed. Treatment complications are evident -panhypogammaglobulinaemia secondary to rituximab treatment and steroid induced osteoporosis/fracture. Case report -Discussion: MCTD was first suggested as a distinct entity in 1972 by Sharp and colleagues. There is a lack of consensus over the four published diagnostic criteria (Kasukawa's, Alarcon-Segovia, Kahn and Sharp), none of which have been validated for use in children.
Heterogeneity of clinical features and the rarity of childhood-onset MCTD makes diagnosis a challenge. Raynaud's phenomenon and polyarthritis are the most common presenting features. It was only with time that the clinical picture of MCTD emerged. There is limited evidence available to guide treatment but emerging evidence of benefit from rituximab. Management aims to minimise active inflammation and treatment toxicitybalancingthe evolving clinical picturewith sideeffects fromtreatments used, as exemplified in these two cases. Given potential evolution to SLE anti-TNF drugs are usually avoided but in case 2 when this appeared phenotypically to be JIA/JDM both etanercept and infliximab were used. In Sheffield transfer usually occurs around the end of school year 11 but for case 1 this was the time of maximum clinical instability. Transition was delayed enabling treatment with rituximab in a familiar environment and transfer only occurredwhendisease was stable. In case 2with suchintensive treatment in paediatric rheumatology transition planning carefully emphasised the clinical features and medicines used which has been of great benefit in adult services to maintain disease control and quiescence and avoid risks of over treatment. An integrated transition pathway from paediatric to adult services has ensured a safety net to the evolving nature of these inflammatory diseases and allowed a joint approach to the diagnosis and management. Case report -Key learning points: Evolution of disease: Paediatriconset MCTD is rare. As paediatric and adolescent rheumatologists we will be seeing patients early in the disease course. We need an awareness of the potential for our inflammatory patients' symptoms to evolve and to re-assess the diagnosis whenthis happens.
Respect anti-RNP antibodies: anti-RNP antibodies, either at disease outset (case 1) or occurring later in disease course (case 2) help distinguish evolving MCTD, presenting with polyarthritis with or without Raynaud's phenomenon, from 'straightforward' polyarticular JIA. Children and young people who have anti-RNP antibodies need to be watched carefully forevolutionof MCTD symptoms.
Integrated Transition: As MCTD may evolve over several years, a close partnership between paediatric and adult rheumatology (whether part of an integrated adolescent transition service or not) helps deliver developmentally appropriate health care. Expect complications: Paediatric onset MCTD tends to have a milder disease course than in adults, although complete remission is rare. The most common causes of death are linked to pulmonary hypertension and interstitial lung disease. However, these complications are less seen in children. Clinical vigilance and proactive screening in watching for development of the disease and trying to anticipate potential problems are important. This requires multi-disciplinary team working. This is just as important when managing treatment effects such as panhypogammaglobulinaemia and liaison with immunology team or steroid side effects and liaison with endocrinology team. Individualised Approach: There is no one specific treatment for MCTD. The heterogeneity of the condition dictates an individualised approach using best available evidence. It is particularly important to review treatment strategies as new symptoms emerge, or side-effects emerge from treatments being used.

Dr Sulaiman Al Habib Medical Group, Riyadh, Saudi Arabia
Case report -Introduction: We present a case of 15-year-old girl referred to rheumatology clinic by Infectious disease consultant in a private hospital. Her presentation included fever, inflammatory joint pains, butterfly rash and finger pulp infarcts. Her immunology showed highly positive anti DsDNA (>1000), positive anti smith and anti Ro antibodies. This case eludes challenges of management as she went on to develop lupus nephritis. She was treated with IV Methylprednisolone pulse therapy followed by tapering course of steroids, Mycophenolate Mofetil Hydroxychloroquine. The immunosuppressive treatment includ cyclophosphamide and Rituximab could not be given due to approval by her insurance provider. Case report -Case description: This 15-yearold Egyptian young presented initially in September 2019 to Emergency department fever and facial rash. This episode was treated as allergic Subsequently, she was referred to see the Infectious disease who requested multiple investigations including blood culture, DsDNA and ENA antibodies. She presented to Rheumatology clinic with malar rash, mouth ulcers, ger pulp infarcts and joint pains. Her Immunology showed ANA Anti DsDNA 1031, Anti Ro 27, Anti Sm 30, Anti nRNP/Sm 28 and Urinary Albumin/Creatinine ratio (27 mg/mmol). A diagnosis of Lupus Erythematosus with Lupus Nephritis was made. She was init on tapering course of steroids (30 mg starting dose) and 400 mg. The follow up visit confirmed improvement (including facial and urine ACR of 17 mg/mmol. The steroids were tapered by 5 mg 2 weeks and Azathioprinewas considered. Unfortunately, she developed renal flare in December 2019 which cided with reduction in steroid. Urine ACR value 383 mg/mmol, ESR and Anti DsDNA was >1000. The request to offer induction therapy Rituximab (as she was not keen for Cyclophosphamide) did not approval byher insurance company. Her case was reviewed by gist, biopsy was not done at this stage. Her condition was managed Mycophenolate and Pulse steroid therapy. In February 2020, she had further renal flare (Urine ACR 694 and that required increase in the dose of steroids. Unfortunately, was still disapproval by insurance company despite multiple Over the course of next 3 months, there was poor compliance with attendance coinciding with COVID-19pandemic. Her included oral Prednisolone 15 mg OD, Mycophenolate 3 gm Hydroxychloroquine400 mg. More recently, she has had significant renal flare treated Nephrologist with Pulse therapy of IV Methylprednisolone with la approval to give Rituximab by her insurance provider. Case report -Discussion: This is a challenging case of Lupus nephr a young adolescent girl seen in a private hospital in Riyadh, Saudi Arabia. She was concerned about her appearance in her first presentation disfiguring facial rash. This rash completely resolved, and patient very satisfied to the extent of some lack of engagement in follow subsequently. This clinic is based in a busy and popular private hospital in Riyadh non-Arabic speaking clinician rely on translator to communicate patient and this can make the consultation further challenging. The cian must make sure, in brief consultation time, to get the exact across. My experience did teach me that there were certain times when medications were not taken as intended due to lack of full understanding by the patient. In a private hospital setting, patient can choose their own compliance with clinic attendance as per their convenience and understanding of the condition. This aspect also contributed towards management challenges and control of her disease. The most limiting and frustrating factor to manage this case has also been the lack of engagement and approval by the insurance provider. I made multiple medical requests for their attention and unfortunately all were rejected. The local healthcare system in Kingdom of Saudi Arabia allows expat patients to be seen primarily in private hospitals under the cover of their employer insurance. This also led to lack of sharing expertise and treatment facilities with the regional specialist rheumatology centre, which is mainly designed to cater for local nationals. I am seriously considering making a "special request" for this case to be accepted in the Ministry hospital so Cyclophosphamide and/or Rituximab can be considered.

Case report -Key learningpoints
Should we have considered Mycophenolate at very initial presentation and could that have led to different and better clinical outcome? Would renal biopsy change management significantly and how best we can persuade patient and Nephrologist? How else we can engage this young adolescent girl as she was more concerned about her cosmetic appearance and since skin has responded very well, she may not feel too convinced on the need for ongoing treatment and also attending clinic appointment? Perhaps we could have referred her case as a "special request" to local specialist Rheumatology center so she could have been considered for treatment options like Rituximab and cyclophosphamide. The local healthcare in Saudi Arabia permits local nationals to be seen in local and private hospitals whilst expats are catered only in private hospital unless there is exception due to availability of treatment or expertise, where process of acceptance can also be