Panel sequencing links rare, likely damaging gene variants with distinct clinical phenotypes and outcomes in juvenile-onset SLE.

OBJECTIVES: Juvenile-onset systemic lupus erythematosus (jSLE) affects 15-20% of lupus patients. Clinical heterogeneity between racial groups, age groups and individual patients suggests variable pathophysiology. This study aimed to identify highly penetrant damaging mutations in genes associated with SLE/SLE-like disease in a large national cohort (UK JSLE Cohort Study) and compare demographic, clinical and laboratory features in patient sub-cohorts with 'genetic' SLE vs remaining SLE patients. METHODS: Based on a sequencing panel designed in 2018, target enrichment and next-generation sequencing were performed in 348 patients to identify damaging gene variants. Findings were integrated with demographic, clinical and treatment related datasets. RESULTS: Damaging gene variants were identified in ∼3.5% of jSLE patients. When compared with the remaining cohort, 'genetic' SLE affected younger children and more Black African/Caribbean patients. 'Genetic' SLE patients exhibited less organ involvement and damage, and neuropsychiatric involvement developed over time. Less aggressive first line treatment was chosen in 'genetic' SLE patients, but more second and third line agents were used. 'Genetic' SLE associated with anti-dsDNA antibody positivity at diagnosis and reduced ANA, anti-LA and anti-Sm antibody positivity at last visit. CONCLUSION: Approximately 3.5% of jSLE patients present damaging gene variants associated with younger age at onset, and distinct clinical features. As less commonly observed after treatment induction, in 'genetic' SLE, autoantibody positivity may be the result of tissue damage and explain reduced immune complex-mediated renal and haematological involvement. Routine sequencing could allow for patient stratification, risk assessment and target-directed treatment, thereby increasing efficacy and reducing toxicity.

Real world treatment of juvenile-onset systemic lupus erythematosus: Data from the UK JSLE cohort study.

BACKGROUND: In the absence of clinical trials evidence, Juvenile-onset Systemic Lupus Erythematosus (JSLE) treatment plans vary. AIM: To explore 'real world' treatment utilising longitudinal UK JSLE Cohort Study data. METHODS: Data collected between 07/2009-05/2020 was used to explore the choice/sequence of immunomodulating drugs from diagnosis. Multivariate logistic regression determined how organ-domain involvement (pBILAG-2004) impacted treatment choice. RESULT: 349 patients met inclusion criteria, median follow-up 4-years (IQR:2,6). Mycophenolate mofetil (MMF) was most commonly used for the majority of organ-domains, and significantly associated with renal involvement (OR:1.99, 95% CI:1.65-2.41, pc < 0.01). Analyses assessing the sequence of immunomodulators focused on 197/349 patients (meeting relevant inclusion/exclusion criteria). 10/197 (5%) solely recieved hydroxychloroquine/prednisolone, 62/197 (31%) received a single-immunomodulator, 69/197 (36%) received two, and 36/197 patients (28%) received ≥three immunomodulators. The most common first and second line immunomodulator was MMF. Rituximab was the most common third-line immunomodulator. CONCLUSIONS: Most UK JSLE patients required ≥two immunomodulators, with MMF used most commonly.

Attainment of low disease activity and remission targets reduces the risk of severe flare and new damage in childhood lupus.

OBJECTIVES: To assess the achievability and effect of attaining low disease activity (LDA) or remission in childhood-onset SLE (cSLE). METHODS: Attainment of three adult-SLE derived definitions of LDA (LLDAS, LA, Toronto-LDA), and four definitions of remission (clinical-SLEDAI-defined remission on/off treatment, pBILAG-defined remission on/off treatment) was assessed in UK JSLE Cohort Study patients longitudinally. Prentice-Williams-Petersen gap recurrent event models assessed the impact of LDA/remission attainment on severe flare/new damage. RESULTS: LLDAS, LA and Toronto-LDA targets were reached in 67%, 73% and 32% of patients, after a median of 18, 15 or 17 months, respectively. Cumulatively, LLDAS, LA and Toronto-LDA was attained for a median of 23%, 31% and 19% of total follow-up-time, respectively. Remission on-treatment was more common (61% cSLEDAI-defined, 42% pBILAG-defined) than remission off-treatment (31% cSLEDAI-defined, 21% pBILAG-defined). Attainment of all target states, and disease duration (>1 year), significantly reduced the hazard of severe flare (P < 0.001). As cumulative time in each target increased, hazard of severe flare progressively reduced. LLDAS attainment reduced the hazard of severe flare more than LA or Toronto-LDA (P < 0.001). Attainment of LLDAS and all remission definitions led to a statistically comparable reduction in the hazards of severe flare (P > 0.05). Attainment of all targets reduced the hazards of new damage (P < 0.05). CONCLUSIONS: This is the first study demonstrating that adult-SLE-derived definitions of LDA/remission are achievable in cSLE, significantly reducing risk of severe flare/new damage. Of the LDA definitions, LLDAS performed best, leading to a statistically comparable reduction in the hazards of severe flare to attainment of clinical remission.

Neuropsychiatric involvement in juvenile-onset systemic lupus erythematosus: Data from the UK Juvenile-onset systemic lupus erythematosus cohort study.

INTRODUCTION: Juvenile-onset systemic lupus erythematosus (JSLE) is a rare autoimmune/inflammatory disease with significant morbidity and mortality. Neuropsychiatric (NP) involvement is a severe complication, encompassing a heterogeneous range of neurological and psychiatric manifestations. METHODS: Demographic, clinical, and laboratory features of NP-SLE were assessed in participants of the UK JSLE Cohort Study, and compared to patients in the same cohort without NP manifestations. RESULTS: A total of 428 JSLE patients were included in this study, 25% of which exhibited NP features, half of them at first visit. Most common neurological symptoms among NP-JSLE patients included headaches (78.5%), mood disorders (48.6%), cognitive impairment (42%), anxiety (23.3%), seizures (19.6%), movement disorders (17.7%), and cerebrovascular disease (14.9%). Peripheral nervous system involvement was recorded in 7% of NP-SLE patients. NP-JSLE patients more frequently exhibited thrombocytopenia (<100 × 109/L) (p = 0.04), higher C-reactive protein levels (p = 0.01), higher global pBILAG score at first visit (p < 0.001), and higher SLICC damage index score at first (p = 0.02) and last (p < 0.001) visit when compared to JSLE patients without NP involvement. CONCLUSIONS: A significant proportion of JSLE patients experience NP involvement (25%). Juvenile-onset NP-SLE most commonly affects the CNS and is associated with increased overall disease activity and damage.

Case of paediatric relapsing polychondritis with severe airway involvement: the challenges of long-term airway and respiratory management.

We describe a case of a 15-year-old girl diagnosed with relapsing polychondritis (RP) with involvement of the tracheobronchial tree, resulting in an increased difficulty in breathing, hoarseness of voice and stridor.Her case required the input of multiple specialities including ear, nose and throat, rheumatology, respiratory team and intensive care. Airway assessment and imaging showed glottic and subglottic stenosis and left bronchomalacia. Despite the use of steroids, cyclophosphamide and rituximab, her symptoms progressed and she was started on overnight non-invasive ventilation.She had further relapses of her airway RP-she was started on adalimumab and methotrexate and underwent monthly balloon dilatations which helped with her symptoms and facilitated a safe discharge home. However, she had further relapses and intensive care admissions and following further discussions, a tracheostomy was inserted. She is now stable on her tracheostomy and is off any respiratory support.

Limited sensitivity and specificity of the ACR/EULAR-2019 classification criteria for SLE in JSLE?-observations from the UK JSLE Cohort Study.

OBJECTIVES: This study aimed to test the performance of the new ACR and EULAR criteria, that include ANA positivity as entry criterion, in JSLE. METHODS: Performance of the ACR/EULAR-2019 criteria were compared with Systemic Lupus International Collaborating Clinics (SLICC-2012), using data from children and young people (CYP) in the UK JSLE Cohort Study (n = 482), with the ACR-1997 criteria used as reference standard. An unselected cohort of CYP positive for ANA (n = 129) was used to calculate positive/negative predictive values of the criteria. RESULTS: At both first and last visits, the number of patients fulfilling the different classification criteria varied significantly (P < 0.001). The sensitivity of the SLICC-2012 criteria was higher when compared with that of the ACR/EULAR-2019 criteria at first and last visits (98% vs 94% for first visit, and 98% vs 96% for last visit; P < 0.001), when all available CYP were considered. The ACR/EULAR-2019 criteria were more specific when compared with the SLICC-2012 criteria (77% vs 67% for first visit, and 81% vs 71% for last visit; P < 0.001). Significant differences between the classification criteria were mainly caused by the variation in ANA positivity across ages. In the unselected cohort of ANA-positive CYP, the ACR/EULAR-2019 criteria produced the highest false-positive classification (6/129, 5%). CONCLUSION: In CYP, the ACR/EULAR-2019 criteria are not superior to those of the SLICC-2012 or ACR-1997 criteria. If classification criteria are designed to include CYP and adult populations, paediatric rheumatologists should be included in the consensus and evaluation process, as seemingly minor changes can significantly affect outcomes.

'It is good to have a target in mind': qualitative views of patients and parents informing a treat to target clinical trial in juvenile-onset systemic lupus erythematosus.

OBJECTIVE: We sought to explore patient and parental views on treatment targets, outcome measures and study designs being considered for a future JSLE treat-to-target (T2T) study. METHODS: We conducted topic-guided, semistructured interviews with JSLE patients and parents and analysed the audio recorded interviews using thematic approaches. RESULTS: Patients and parents differed regarding symptoms they felt would be tolerable, representing 'low disease activity'. Patients often classed symptoms that they had previously experienced, were 'invisible' or had minimal disruption on their life as signs of low disease activity. Parents were more accepting of visible signs but were concerned about potential organ involvement and symptom severity. Overall, patients and parents preferred that children were entirely asymptomatic, with no ongoing treatment side effects. They regarded fatigue as particularly challenging, requiring proper monitoring using a fatigue patient-reported outcome measure. Most families felt that reducing corticosteroids would also be a good treatment target. Overall, families liked the concept of T2T, commenting that it could help to improve disease control, help structure treatment and improve communication with clinicians and treatment compliance. They were concerned that T2T might increase the frequency of hospital visits, thus impacting upon schooling, parental employment and finances. Families made suggestions on how to modify the future trial design to mitigate such effects. CONCLUSION: This study provides guidance from patients and parents on T2T targets and study designs. Complementary quantitative studies assessing the achievability and impact of different targets (e.g. lupus low disease activity state or remission) are now warranted to inform an international consensus process to develop treatment targets.

Clinical and laboratory phenotypes in juvenile-onset Systemic Lupus Erythematosus across ethnicities in the UK.

Systemic lupus erythematosus (SLE) is a systemic autoimmune/inflammatory disease. Patients diagnosed with juvenile-onset SLE (jSLE), when compared to individuals with adult-onset SLE, develop more severe organ involvement, increased disease activity and greater tissue and organ damage. In adult-onset SLE, clinical characteristics, pathomechanisms, disease progression and outcomes do not only vary between individuals and age groups, but also ethnicities. However, in children and young people, the influence of ethnicity on disease onset, phenotype and outcome has not been investigated in detail. In this study, we investigated clinical and laboratory characteristics in pediatric SLE patients from different ethnic backgrounds (White Caucasian, Asian, Black African/Caribbean) accessing data from a national cohort of jSLE patients (the UK JSLE Cohort Study). Among jSLE patients in the UK, ethnicity affects both the disease's clinical course and outcomes. At diagnosis, Black African/Caribbean jSLE patients show more "classical" laboratory and clinical features when compared to White Caucasian or Asian patients. Black African/Caribbean jSLE patients exhibit more renal involvement and more frequently receive cyclophosphamide and rituximab. Studies targeting ethnicity-specific contributors to disease expression and phenotypes are necessary to improve our pathophysiological understanding, diagnosis and treatment of jSLE.

Unusual Presentation of Intrasacral Meningocele: A Case Report and Overview.

Intrasacral meningocele is an unusual congenital lesion. It is an intrathecal cystic formation arising as a protrusion of the arachnoid through a congenitally weak place in the dura mater. We report a case of a 12-year-old child with chronic pain with an intrasacral meningocele identified on magnetic resonance imaging.

Cluster of human parechovirus infections as the predominant cause of sepsis in neonates and infants, Leicester, United Kingdom, 8 May to 2 August 2016.

We report an unusually high number of cases (n = 26) of parechovirus infections in the cerebrospinal fluid (CSF) of neonates and infants admitted with sepsis in the United Kingdom during 8 May to 2 August 2016. Although such infections in neonates and infants are well-documented, parechovirus has not been routinely included in many in-house and commercial PCR assays for CSF testing. Clinicians should consider routine parechovirus testing in young children presenting with sepsis.

Acute longitudinal myelitis as the first presentation in child with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a multi-system auto-immune disorder that is characterized by widespread immune dysregulation, formation of auto-antibodies, and immune complexes, resulting in inflammation and potential damage to variety of organs. It is complicated by neurological manifestations in 25-95% of the patients. Acute transverse myelitis (ATM) may be a complication in 1-2% of patients with SLE but in some patients it may be the initial manifestation of SLE. This sub-group of patients where ATM is the presenting feature may not fulfil the ACR criteria for the diagnosis of SLE which may delay the diagnosis and may affect the outcome. In those patients where the involvement is more than four segments of the spine are believed to have poor prognosis, but early diagnosis and treatment may alter the course and lead to a better outcome. We describe a young Polish girl where ATM was the initial manifestation of SLE involving almost the whole length of spine but she had a reasonably good outcome following early diagnosis and aggressive treatment.

Tuberculous radiculomyelitis presenting as urinary retention in a child with Down's syndrome.

Tuberculous radiculomyelitis (TBRM) is an uncommon complication of TB meningitis. The authors report the case of a 10-year-old Asian girl with trisomy 21, who presented with acute urinary retention and fever. She was initially treated for a urinary tract infection. After an acute neurological deterioration she was found to have evidence of TB meningitis with TBRM. She developed acute hydrocephalus requiring ventriculo-peritoneal shunt. She was treated with quadruple antituberculous therapy and high dose intravenous dexamethasone. She needed tracheostomy with continuous positive airway pressure (CPAP) support. Although she showed gradual neurological improvement in her cognitive functions, she persisted to have quadriparesis with the need for tracheostomy and CPAP support overnight and gastrostomy feeding. Acute urinary retention in children is uncommon, and should serve as a 'red flag' to consideration of further underlying neurological problems. This presentation and subsequent events should serve as a learning point to clinicians.

Bilateral thoracic outlet syndrome: An uncommon presentation of a rare condition in children.

We report an adolescent girl who had left-sided neurogenic thoracic outlet syndrome (TOS) due to impingement of the scalenus anterior muscle with bilateral changes on nerve conduction studies and responded well to surgical decompression. A 13-year-old Caucasian girl presented with intermittent pain, swelling, erythema, tingling and numbness of the palmar aspect of her left hand. Nerve conduction studies revealed bilateral ulnar sensory and motor conduction abnormalities, suggesting early compressive neuropathy in the asymptomatic arm as well. She underwent surgical exploration when it was noted that the scalenus anterior itself was impinging on the brachial plexus. She had a good clinical response to scalenectomy. The diagnosis of neurogenic TOS remains difficult as no single test has been accepted as a gold standard. But, once diagnosed using clinical symptoms, nerve conduction studies, electromyography and radiological investigations, it is a treatable condition with good prognosis.

A 4-year-old boy with post-traumatic winging of the scapula.

The authors report the case of a 4-year-old boy who presented to the emergency department with acute post-traumatic winging of right scapula following a fall onto his back. The x-ray of his right shoulder showed no fracture. An MRI Scan of cervical spine and brachial plexus did not reveal any abnormalities. He was managed conservatively with regular physiotherapy. At 2 years follow-up, there was no improvement in the winging of his right scapula. He was asymptomatic at rest but complains of pain in the right scapular and shoulder region during swimming limiting his swimming activity. Currently he was being evaluated by the orthopaedic team for corrective surgery.

A 4-year-old boy with post-traumatic winging of the scapula.

The authors report the case of a 4-year-old boy who presented to the emergency department with acute post-traumatic winging of right scapula following a fall onto his back. The x-ray of his right shoulder showed no fracture. An MRI Scan of cervical spine and brachial plexus did not reveal any abnormalities. He was managed conservatively with regular physiotherapy. At 2 years follow-up, there was no improvement in the winging of his right scapula. He was asymptomatic at rest but complains of pain in the right scapular and shoulder region during swimming limiting his swimming activity. Currently he was being evaluated by the orthopaedic team for corrective surgery.