Genetic testing of Behçet’s disease using next-generation sequencing to identify monogenic mimics and HLA-B*51

Objective: Several monogenic autoinflammatory disorders and primary immunodeficiencies can present early in life with features that may be mistaken for Behçet's disease (BD). We aimed to develop a genetic analysis workflow to identify rare monogenic BD-like diseases and establish the contribution of HLA haplotype in a cohort of patients from the UK. // Methods: Patients with clinically suspected BD were recruited from four BD specialist care centres in the UK. All participants underwent whole exome sequencing (WES), and genetic analysis thereafter by 1. examining genes known to cause monogenic immunodeficiency, autoinflammation or vasculitis by virtual panel application; 2. scrutiny of variants prioritised by Exomiser using Human Phenotype Ontology (HPO); 3. identification of copy number variants using ExomeDepth; and 4. HLA-typing using OptiType. // Results: Thirty-one patients were recruited: median age 15 (4-52), and median disease onset age 5 (0-20). Nine/31 (29%) patients had monogenic disease mimicking BD: 5 cases of Haploinsufficiency of A20 with novel TNFAIP3 variants (p.T76I, p.M112Tfs*8, p.S548Dfs*128, p.C657Vfs*14, p.E661Nfs*36); 1 case of ISG15 deficiency with a novel nonsense variant (ISG15:p.Q16X) and 1p36.33 microdeletion; 1 case of Common variable immune deficiency (TNFRSF13B:p.A181E); and 2 cases of TNF receptor associated periodic syndrome (TNFRSF1A:p.R92Q). Of the remaining 22 patients, 8 (36%) were HLA-B*51 positive. // Conclusion: We describe a novel genetic workflow for BD, which can efficiently detect known and potentially novel monogenic forms of BD, whilst additionally providing HLA-typing. Our results highlight the importance of genetic testing before BD diagnosis, since this has impact on choice of therapy, prognosis, and genetic counselling

“It is good to have a target in mind”: Qualitative views of patients and parents informing a treat to target clinical trial in JSLE

Abstract Objective We sought to explore patient and parental views on treatment targets, outcome measures and study designs being considered for a future juvenile-onset systemic lupus erythematosus (JSLE) treat to target (T2T) study. Methods Topic guided, semi-structured interviews with JSLE patients/parents. Analysis of 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 on-going 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, structure treatment, 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/parents on T2T targets and study designs. Complementary quantitative studies assessing the achievability and impact of different targets (e.g. LLDAS or remission) are now warranted, to inform an international consensus process to agree treatment targets. </jats:sec

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

Funder: LUPUS UKSystemic 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

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

Funder: LUPUS UKSystemic 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

American College of Rheumatology Provisional Criteria for Clinically Relevant Improvement in Children and Adolescents With Childhood-Onset Systemic Lupus Erythematosus

10.1002/acr.23834ARTHRITIS CARE & RESEARCH715579-59

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

PSTPIP1-associated myeloid-related proteinaemia inflammatory (PAMI) syndrome; a case presenting as a perinatal event with early central nervous system involvement?

Abstract Background We report a three-year-old girl with a potentially unique phenotype of perinatal onset and neurovascular features who was found to have PAMI syndrome. We also compare her case to those previously reported and review the differences between the PSTPIP1-associated inflammatory diseases (PAID) phenotypes and genotypes. Case presentation The patient was found to have a heterozygous pathogenic variant in PSTPIP1 (c.748G > A p.E250K). This variant was shown to be absent in both parents and therefore de novo in the patient. A literature review was carried out through multiple databases using the terms PSTPIP1, PAID, PAPA syndrome and PAMI syndrome. This information was collected and used to form comparisons between the current literature and our reported case. Conclusions Our case contributes to the literature on PAMI syndrome whilst providing an example of a potentially unique clinical phenotype, giving insight into the pre-symptomatic phase of the condition. We highlight the importance of considering PAMI syndrome in the differential for early onset unexplained inflammation. In addition, we explore the possibility that perinatal neurovascular events could be an early feature of PAMI syndrome

Juvenile Dermatomyositis Magnetic Resonance Imaging Score (JIS) does not correlate with criteria for clinically inactive disease:a single-centre retrospective evaluation

The Paediatric Rheumatology International Trials Organisation (PRINTO) criteria for clinically inactive disease (CID) and their proposal for glucocorticoid tapering do not consider MRI findings, despite the growing use of MRI and development of reliable MRI scoring tools. We aim to evaluate how CID correlates with MRI scores and physician decision making. We retrospectively used the Juvenile Dermatomyositis Imaging Score (JIS) to score MRIs of all children with JDM over a 10-year period. Demographic, diagnosis, treatment and core set measures data were collected. Correlation between CID and JIS was assessed as well as correlation with the physician treatment decision. There were 25 patients with 59 follow-up episodes to analyse correlation between physician treatment decision and JIS; and 50 episodes for the CID category and JIS correlation. JIS was not significantly associated with the CID category but did correlate with the physician decision. No significant association was found between clinical decision and CID category. The JIS area under the ROC curve (AUC) was 0.80 (95% CI 0.62–0.99) with a score ≥ 8 to predict an escalation. JIS sensitivity and specificity were both 78% with accuracy of 78%, compared to only 67%, 46% and 49%, respectively, for the CID criteria. Clinical criteria alone are not sufficient to assess disease activity status. Clinical decision trends correlated to MRI findings but not PRINTO CID criteria. Multi centre prospective studies are needed to replicate our findings and establish how to best use MRI as a biomarker of disease activity. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00296-021-05049-1

Vitamin D status of children with Paediatric Inflammatory Multisystem Syndrome Temporally associated with Severe acute respiratory syndrome coronavirus 2 (PIMS-TS).

Coronavirus disease 2019 (COVID-19), has caused mild illness in children, until the emergence of the novel hyperinflammatory condition PIMS-TS: Paediatric Inflammatory Multisystem Syndrome Temporally associated with Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). PIMS-TS is thought to be a post- SARS-CoV-2 immune dysregulation with excessive inflammatory cytokine release. We studied 25 hydroxyvitamin D (25OHD) concentrations in children with PIMS-TS, admitted to a tertiary paediatric hospital in the United Kingdom (U.K), due to its postulated role in cytokine regulation and immune response. Eighteen children [median (range) age 8.9 (0.3 to 14.6) years, male=10] met the case definition. Majority were of Black, Asian and Minority Ethnic (BAME) origin [89%, 16/18]. Positive SARS-CoV-2 IgG antibodies were present in 94% (17/18) and RNA by PCR in 6% (1/18). 72% of the cohort were vitamin D deficient (<30nmol/L). The mean 25OHD concentration was significantly lower when compared to the population mean from the 2015/16 National Diet and Nutrition Survey (children aged 4-10 years) [24 vs 54nmol/L (95% CI: -38.6, -19.7); p<0.001]. The PICU group had lower mean 25OHD concentrations compared to the non-PICU group, but this was not statistically significant [19.5 vs 31.9 nmol/L; p=0.11]. The higher susceptibility of BAME children to PIMS-TS and also vitamin D deficiency merits contemplation. Whilst any link between vitamin D deficiency and the severity of COVID-19 and related conditions including PIMS-TS requires further evidence, public health measures to improve vitamin D status of the U.K BAME population has been long overdue

Paediatric Inflammatory Multisystem Syndrome: Temporally Associated with SARS-CoV-2 (PIMS-TS): Cardiac Features, Management and Short-Term Outcomes at a UK Tertiary Paediatric Hospital.

Children were relatively spared during COVID-19 pandemic. However, the recently reported hyperinflammatory syndrome with overlapping features of Kawasaki disease and toxic shock syndrome-"Paediatric Inflammatory Multisystem Syndrome-temporally associated with SARS-CoV-2" (PIMS-TS) has caused concern. We describe cardiac findings and short-term outcomes in children with PIMS-TS at a tertiary children's hospital. Single-center observational study of children with PIMS-TS from 10th April to 9th May 2020. Data on ECG and echocardiogram were retrospectively analyzed along with demographics, clinical features and blood parameters. Fifteen children with median age of 8.8 (IQR 6.4-11.2) years were included, all were from African/Afro-Caribbean, South Asian, Mixed or other minority ethnic groups. All showed raised inflammatory/cardiac markers (CRP, ferritin, Troponin I, CK and pro-BNP). Transient valve regurgitation was present in 10 patients (67%). Left Ventricular ejection fraction was reduced in 12 (80%), fractional shortening in 8 (53%) with resolution in all but 2. Fourteen (93%) had coronary artery abnormalities, with normalization in 6. ECG abnormalities were present in 9 (60%) which normalized in 6 by discharge. Ten (67%) needed inotropes and/or vasopressors. None needed extracorporeal life support. Improvement in cardiac biochemical markers was closely followed by improvement in ECG/echocardiogram. All patients were discharged alive and twelve (80%) have been reviewed since. Our entire cohort with PIMS-TS had cardiac involvement and this degree of involvement is significantly more than other published series and emphasizes the need for specialist cardiac review. We believe that our multi-disciplinary team approach was crucial for the good short-term outcomes