Carole Cummins

INCIDENCE OF HENOCH-SCHONLEIN PURPURA, KAWASAKI DISEASE, AND RARE VASCULITIDES IN CHILDREN OF DIFFERENT ETHNIC ORIGINS

BACKGROUND The frequency and ethnic variation of Henoch-Schönlein purpura, Kawasaki disease, and rarer vasculitides during childhood are not well characterised. Our aim was to ascertain the incidence and ethnic distribution of these conditions in children resident in a region of the UK with a diverse ethnic mix. METHODS 1.1 million children younger than age 17 years live in the West Midlands. Between Sept 1, 1996, and Aug 31, 1999, we surveyed this population with monthly questionnaires sent to 321 consultants, a single questionnaire sent to 2860 family doctors, and review of 406 case notes with diagnostic codes for vasculitis. We included in the analyses children who fulfilled established criteria for vasculitis with disease onset during the study, and calculated incidence rates from population rates derived from the census of 1991. FINDINGS We identified 586 new instances of vasculitis and connective tissue disease. The estimated annual incidence of Henoch-Schönlein purpura was 20.4 per 100000, and was highest between the ages of 4 years and 6 years (70.3 per 100000). The estimated annual incidence of Kawasaki disease was 5.5 per 100000 in children younger than 5 years, and was highest in Indian subcontinent Asian children (14.6 per 100000). Indian subcontinent Asian and black children had the highest incidence of systemic lupus erythematosus, juvenile dermatomyositis, and other primary systemic vasculitides. INTERPRETATION Childhood Henoch-Schönlein purpura is more frequent in the West Midlands than previously reported, and Kawasaki disease has a higher incidence than previously indicated in the UK, with the highest incidence in Indian subcontinental Asian children. Other vasculitis is rare in childhood.

The effectiveness of the levonorgestrel‐releasing intrauterine system in menorrhagia: a systematic review

Objective To determine whether the levonorgestrel‐releasing intrauterine device (LNG‐IUS), licensed at present for contraceptive use, may reduce menstrual blood loss with few side effects. If effective, surgery could be avoided with consequent resource savings.

Prevalence and Predictors of Vitamin D Insufficiency in Children: A Great Britain Population Based Study

Objectives To evaluate the prevalence and predictors of vitamin D insufficiency (VDI) in children In Great Britain. Design A nationally representative cross-sectional study survey of children (1102) aged 4–18 years (999 white, 570 male) living in private households (January 1997–1998). Interventions provided information about dietary habits, physical activity, socio-demographics, and blood sample. Outcome measures were vitamin D insufficiency (<50 nmol/L). Results Vitamin D levels (mean = 62.1 nmol/L, 95%CI 60.4–63.7) were insufficient in 35%, and decreased with age in both sexes (p<0.001). Young People living between 53–59 degrees latitude had lower levels (compared with 50–53 degrees, p = 0.045). Dietary intake and gender had no effect on vitamin D status. A logistic regression model showed increased risk of VDI in the following: adolescents (14–18 years old), odds ratio (OR) = 3.6 (95%CI 1.8–7.2) compared with younger children (4–8 years); non white children (OR = 37 [95%CI 15–90]); blood levels taken December-May (OR = 6.5 [95%CI 4.3–10.1]); on income support (OR = 2.2 [95%CI 1.3–3.9]); not taking vitamin D supplementation (OR = 3.7 [95%CI 1.4–9.8]); being overweight (OR 1.6 [95%CI 1.0–2.5]); <1/2 hour outdoor exercise/day/week (OR = 1.5 [95%CI 1.0–2.3]); watched >2.5 hours of TV/day/week (OR = 1.6[95%CI 1.0–2.4]). Conclusion We confirm a previously under-recognised risk of VDI in adolescents. The marked higher risk for VDI in non-white children suggests they should be targeted in any preventative strategies. The association of higher risk of VDI among children who exercised less outdoors, watched more TV and were overweight highlights potentially modifiable risk factors. Clearer guidelines and an increased awareness especially in adolescents are needed, as there are no recommendations for vitamin D supplementation in older children.

Systematic review and meta-analysis of evidence for increasing numbers of drugs in antiretroviral combination therapy

Abstract Objective: To assess the evidence for the effectiveness of increasing numbers of drugs in antiretroviral combination therapy. Design: Systematic review, meta-analysis, and meta-regression of fully reported randomised controlled trials. All studies included compared quadruple versus triple therapy, triple versus double therapy, double versus monotherapy, or monotherapy versus placebo or no treatment. Participants: Patients with any stage of HIV infection who had not received antiretroviral therapy. Main outcome measures: Changes in disease progression or death (clinical outcomes); CD4 count and plasma viral load (surrogate markers). Search strategy: Six electronic databases, including Medline, Embase, and the Cochrane Library, searched up to February 2001. Results: 54 randomised controlled trials, most of good quality, with 66 comparison groups were included in the analysis. For both the clinical outcomes and surrogate markers, combinations with up to and including three (triple therapy) were progressively and significantly more effective. The odds ratio for disease progression or death for triple therapy compared with double therapy was 0.6 (95% confidence interval 0.5 to 0.8). Heterogeneity in effect sizes was present in many outcomes but was largely related to the drugs used and trial quality. Conclusions: Evidence from randomised controlled trials supports the use of triple therapy. Research is needed on the effectiveness of quadruple therapies and the relative effectiveness of specific combinations of drugs. What is already known on this topic Triple combination antiretroviral therapy is accepted by clinicians and patients as the usual treatment for HIV and has evolved through an incremental strategy in the numbers of drugs combined Guidance on treatment, however, has predominantly been based on early reports of research There are no published analyses that assess the effectiveness of the increasing numbers of drugs used in combination What this study adds The results of this systematic review support the use of triple therapy but there is inadequate evidence for quadruple or higher combinations Heterogeneity in the effect estimates seems to result from variable effectiveness of different drug combinations, trial duration, and problems with study quality

Duration of etanercept treatment and reasons for discontinuation in a cohort of juvenile idiopathic arthritis patients

OBJECTIVE Since 2004, juvenile idiopathic arthritis (JIA) patients treated with etanercept and/or MTX have been monitored in the British Society for Paediatric and Adolescent Rheumatology Biologics and New Drug Register. Here, we report the duration of etanercept use for the first 5 years of the register and reasons for discontinuation. METHODS Disease subtype and activity, comorbidity, treatment efficacy and safety data were recorded. Etanercept discontinuation was defined as stopping the drug because of disease remission or treatment failure. Time to discontinuation was explored using Kaplan-Meier survival analysis with remaining patients censored at 5-year follow-up. RESULTS A total of 483 etanercept-treated JIA patients were enrolled from 30 UK centres, representing 941 patient-years of follow-up. A total of 100 (20.7%) patients discontinued etanercept; 9 due to disease control, 88 because of treatment failure, 2 for unknown reasons and 1 because of a change in diagnosis. Of the 53 patients in whom etanercept was perceived to be ineffective at controlling the inflammation, 48 were prescribed other biologic drugs [26/48 (54%) infliximab]. In 21 patients with intolerance, infections, CNS events and a few isolated events were associated with discontinuation. Using Kaplan-Meier analysis, at 5 years 69% (95% CI 61, 77%) had not experienced treatment failure. Discontinuation of etanercept for inefficacy was associated with systemic arthritis subtype [odds ratio (OR) 2.55, 95% CI 1.27, 5.14], chronic anterior uveitis (OR 2.39, 95% CI 1.06, 5.35) and inefficacy of MTX before starting etanercept (OR 8.3, 95% CI 1.14, 60.58). CONCLUSIONS In a cohort of JIA patients treated with etanercept and followed for a median of 2 years (maximum 5 years), the majority (69%) remain on the drug.

Paediatric acquired demyelinating syndromes: incidence, clinical and magnetic resonance imaging features

Objective: Changing trends in multiple sclerosis (MS) epidemiology may first be apparent in the childhood population affected with first onset acquired demyelinating syndromes (ADSs). We aimed to determine the incidence, clinical, investigative and magnetic resonance imaging (MRI) features of childhood central nervous system ADSs in the British Isles for the first time. Methods: We conducted a population active surveillance study. All paediatricians, and ophthalmologists (n = 4095) were sent monthly reporting cards (September 2009–September 2010). International Paediatric MS Study Group 2007 definitions and McDonald 2010 MS imaging criteria were used for acute disseminated encephalomyelitis (ADEM), clinically isolated syndrome (CIS) and neuromyelitis optica (NMO). Clinicians completed a standard questionnaire and provided an MRI copy for review. Results: Card return rates were 90%, with information available for 200/222 positive notifications (90%). After exclusion of cases, 125 remained (age range 1.3–15.9), with CIS in 66.4%, ADEM in 32.0% and NMO in 1.6%. The female-to-male ratio in children older than 10 years (n = 63) was 1.52:1 (p = 0.045). The incidence of first onset ADS in children aged 1–15 years old was 9.83 per million children per year (95% confidence interval [CI] 8.18–11.71). A trend towards higher incidence rates of ADS in children of South Asian and Black ethnicity was observed compared with White children. Importantly, a number of MRI characteristics distinguished ADEM from CIS cases. Of CIS cases with contrast imaging, 26% fulfilled McDonald 2010 MS diagnostic criteria. Conclusions: We report the highest surveillance incidence rates of childhood ADS. Paediatric MS diagnosis at first ADS presentation has implications for clinical practice and clinical trial design.

Autoantibody biomarkers in childhood-acquired demyelinating syndromes: results from a national surveillance cohort

Background Autoantibodies to glial, myelin and neuronal antigens have been reported in a range of central demyelination syndromes and autoimmune encephalopathies in children, but there has not been a systematic evaluation across the range of central nervous system (CNS) autoantibodies in childhood-acquired demyelinating syndromes (ADS). Methods Children under the age of 16 years with first-episode ADS were identified from a national prospective surveillance study; serum from 65 patients had been sent for a variety of diagnostic tests. Antibodies to astrocyte, myelin and neuronal antigens were tested or retested in all samples. Results Fifteen patients (23%) were positive for at least one antibody (Ab): AQ4-Ab was detected in three; two presenting with neuromyelitis optica (NMO) and one with isolated optic neuritis (ON). Myelin oligodendrocyte glycoprotein (MOG)-Ab was detected in seven; two with acute disseminated encephalomyelitis (ADEM), two with ON, one with transverse myelitis (TM) and two with clinically isolated syndrome (CIS). N-Methyl-D-Aspartate receptor (NMDAR)-Ab was found in two; one presenting with ADEM and one with ON. Voltage-gated potassium channel (VGKC)-complex antibodies were positive in three; one presenting with ADEM, one with ON and one with CIS. GlyR-Ab was detected in one patient with TM. All patients were negative for the VGKC-complex-associated proteins LGI1, CASPR2 and contactin-2. Conclusions A range of CNS-directed autoantibodies were found in association with childhood ADS. Although these antibodies are clinically relevant when associated with the specific neurological syndromes that have been described, further studies are required to evaluate their roles and clinical relevance in demyelinating diseases.

The management of squamous cell vulval cancer: a population based retrospective study of 411 cases

Objective To audit the epidemiology, management and outcome of vulval cancer in the West Midlands.

Childhood optic neuritis clinical features and outcome

Aim To describe clinical features and outcome of a series of children with first-episode optic neuritis investigated in three paediatric neurology centres. Methods Databases were searched to identify children (<16 years) with optic neuritis and life table analysis was used. Results 44 children (female/male ratio 1.8) median age 10.9 years were followed up for median 1 year. Optic neuritis was unilateral in 43%. Maximal visual deficit was severe (<6/60) in 77%, with full recovery in 70%. Cumulative probability of developing MS (11/44) or NMO (3/44) at 2 years was 0.45. Relapsing optic neuritis was a strong predictor for development of MS or NMO. A positive MRI (>1 brain T2 hyperintense lesion) was a strong predictor for development of MS. Discussion Childhood optic neuritis is associated with severe visual deficit with good recovery. An initial abnormal MRI brain scan or relapsing optic neuritis should alert the clinician to MS or NMO diagnosis.

Magnetic resonance spectroscopy metabolite profiles predict survival in paediatric brain tumours

Background Brain tumours cause the highest mortality and morbidity rate of all childhood tumour groups and new methods are required to improve clinical management. 1H magnetic resonance spectroscopy (MRS) allows non-invasive concentration measurements of small molecules present in tumour tissue, providing clinically useful imaging biomarkers. The primary aim of this study was to investigate whether MRS detectable molecules can predict the survival of paediatric brain tumour patients. Patients and methods Short echo time (30 ms) single voxel 1H MRS was performed on children attending Birmingham Children’s Hospital with a suspected brain tumour and 115 patients were included in the survival analysis. Patients were followed-up for a median period of 35 months and Cox-Regression was used to establish the prognostic value of individual MRS detectable molecules. A multivariate model of survival was also investigated to improve prognostic power. Results Lipids and scyllo-inositol predicted poor survival whilst glutamine and N-acetyl aspartate predicted improved survival (p < 0.05). A multivariate model of survival based on three MRS biomarkers predicted survival with a similar accuracy to histologic grading (p < 5e–5). A negative correlation between lipids and glutamine was found, suggesting a functional link between these molecules. Conclusions MRS detectable biomolecules have been identified that predict survival of paediatric brain tumour patients across a range of tumour types. The evaluation of these biomarkers in large prospective studies of specific tumour types should be undertaken. The correlation between lipids and glutamine provides new insight into paediatric brain tumour metabolism that may present novel targets for therapy.