Louise Watson

Disease activity, severity, and damage in the UK juvenile-onset systemic lupus erythematosus cohort

OBJECTIVE The UK Juvenile-Onset Systemic Lupus Erythematosus (JSLE) Cohort Study is a multicenter collaborative network established with the aim of improving the understanding of juvenile SLE. The present study was undertaken to describe the clinical manifestations and disease course in patients with juvenile SLE from this large, national inception cohort. METHODS Detailed data on clinical phenotype were collected at baseline and at regular clinic reviews and annual followup assessments in 232 patients from 14 centers across the UK over 4.5 years. Patients with SLE were identified according to the American College of Rheumatology (ACR) SLE classification criteria. The present cohort comprised children with juvenile SLE (n=198) whose diagnosis fulfilled ≥4 of the ACR criteria for SLE. RESULTS Among patients with juvenile SLE, the female:male sex distribution was 5.6:1 and the median age at diagnosis was 12.6 years (interquartile range 10.4-14.5 years). Male patients were younger than female patients (P<0.01). Standardized ethnicity data demonstrated a greater risk of juvenile SLE in non-Caucasian UK patients (P<0.05). Scores on the pediatric adaptation of the 2004 British Isles Lupus Assessment Group disease activity index demonstrated significantly increased frequencies of musculoskeletal (82%), renal (80%), hematologic (91%), immunologic (54%), and neurologic (26%) involvement among the patients over time. A large proportion of the patients (93%) were taking steroids and 24% of the patients required treatment with cyclophosphamide. Disease damage was common, with 28% of the patients having a Systemic Lupus International Collaborating Clinics/ACR damage score of ≥1. CONCLUSION The data on these patients from the UK JSLE Cohort Study, comprising one of the largest national inception cohorts of patients with juvenile SLE to date, indicate that severe organ involvement and significant disease activity are primary characteristics in children with juvenile SLE. In addition, accumulation of disease-associated damage could be seen.

Urinary Monocyte Chemoattractant protein 1 and Alpha-1-acid glycoprotein as biomarkers of renal disease activity in Juvenile-onset Systemic Lupus Erythematosus

A higher proportion of patients with juvenile-onset systemic lupus erythematosus (JSLE) will have renal involvement compared with adult-onset disease, some progressing to renal failure in adulthood. Histological examination is the gold standard for diagnosing lupus nephritis (LN), but its invasive nature limits routine use. Using cross-sectional cohort analysis, we aimed to determine whether urinary concentrations of monocyte chemoattractant protein-1 (MCP1), alpha-1-acid glycoprotein (AGP) and interferon-inducible protein 10 (IP10) are biomarkers of active LN. Sixty JSLE patients recruited to the UK JSLE Cohort Study were categorized according to the British Isles Lupus Assessment Group (BILAG) activity index. Patients with active renal JSLE (n = 8; renal BILAG score A, B) had significantly higher urinary MCP1 concentrations than patients with inactive renal disease (n = 52; renal BILAG score C, D, E; 582 pg/mg creatinine [Cr], 207 pg/mg Cr; p = 0.018) or healthy controls (n = 23; 117 pg/mg Cr; p = 0.005). Urinary AGP concentration was significantly elevated in patients with active renal disease compared with inactive renal disease (1517 ng/mg Cr, 485 ng/mg Cr; p = 0.027) or healthy controls (313 ng/mg Cr; p = 0.013). Urinary IP10 concentration was not significantly different between groups, but did strongly correlate with uMCP and uAGP levels (rho = 0.38, p = 0.009; rho = 0.33, p = 0.021). Urinary MCP1 and AGP are biomarkers of LN, providing insight into its pathophysiology. Longitudinal studies are warranted.

The indications, efficacy and adverse events of rituximab in a large cohort of patients with juvenile-onset SLE

Background B cells drive antibody formation and T cell activation. This study aimed to describe the clinical indications, efficacy and adverse events (AEs) for the B-cell depleting agent, rituximab, in a large cohort of children with lupus. Methods Prescribing records and the UK JSLE Cohort Study database identified rituximab use. Results Sixty-three patients received 104 courses of intravenous rituximab over a 10-year period. Patients were aged 12.2 (IQR 9.0–13.9) years at diagnosis and 50 (79%) were female. They had disease for 1.4 (0.2–3.0) years at the time of rituximab. Lupus nephritis was the most common indication (36% of first courses). Clinical biomarkers, 2.5 (1.6–4.3) months after treatment, demonstrated a statistically significant improvement in ESR, C3, C4, creatinine, albumin, haemoglobin, anti-dsDNA titres and urine albumin:creatinine ratio. IgG, IgA and IgM levels decreased (p < 0.01). Oral corticosteroid dose significantly reduced after rituximab (dose before 0.26 (0.09–0.44) mg/kg, after 0.17 (0.09–0.30) mg/kg; p = 0.01)). AEs occurred in 19 (18%) of all courses including; delayed second dose (8%), Ig replacement (2%) and infusion reactions (6%; anaphylaxis 2%). The global BILAG score showed a trend toward improvement (before 4.5 (2.0–9.0), after 3.0 (2.0–5.0); p = 0.16). Conclusion Rituximab improves disease activity in children with lupus and serious AEs are infrequent. Controlled studies are required.

Children and adolescents with SLE: not just little adults:

Juvenile-onset systemic lupus erythematosus (JSLE) represents 15–20% of all SLE cases. Whilst features of this chronic complex multisystem autoimmune disorder are highly variable, children and adolescents generally present with a more severe illness than adults and accrue greater disease damage over time. JSLE has a less striking female preponderance and differs from the adult form in pattern of major organ manifestations. Corticosteroids are used in almost all children with JSLE along with the majority requiring additional immunosuppressive medications. Making the diagnosis early and optimizing disease control are essential to ensure that normal childhood and adolescent development is not impeded. In this young population, special consideration must be given to the long-term sequelae of the disease and treatment-related toxicity. There is a current lack of paediatric-specific controlled trials and treatment strategies are generally guided by adult data. The enormous psychological and social impact of the disease and its treatments upon the child or young person and their family necessitates a comprehensive, holistic, specialized multidisciplinary approach to managing JSLE.

Henoch Schonlein Purpura – A 5-Year Review and Proposed Pathway

Henoch Schonlein Purpura (HSP) is the commonest systemic vasculitis of childhood typically presenting with a palpable purpuric rash and frequently involving the renal system. We are the first group to clinically assess, critically analyse and subsequently revise a nurse led monitoring pathway for this condition. A cohort of 102 children presenting with HSP to a secondary/tertiary level UK paediatric hospital over a five year period, were monitored using a nurse led care pathway. Using this cohort, the incidence (6.21 cases per 100,000 children per year) and natural disease course of HSP nephritis (46% initial renal inflammation; 9% subsequent renal referral; 1% renal biopsy and immunosuppression) was determined. Older patients were at higher risk of requiring a renal referral (renal referral 12.3 (8.4–13.5) years vs. normal outcome 6.0 (3.7–8.5) years; p<0.01). A normal urinalysis on day 7 had a 97% (confidence interval 90 to 99%) negative predictive value in predicting a normal renal outcome. Using this data and existing literature base, The Alder Hey Henoch Schonlein Purpura Pathway was developed, a revised pathway for the screening of poor renal outcome in HSP. This is based on a six-month monitoring period for all patients presenting with HSP, which importantly prioritises patients according to the urine findings on day 7 and thus intensively monitors those at higher risk of developing nephritis. The pathway could be easily adapted for use in different settings and resources. The introduction of a standardised pathway for the monitoring of HSP will facilitate the implementation of disease registries to further our understanding of the condition and permit future clinical trials.

Unmet needs in the measurement of blood pressure in primary care

Background Blood pressure (BP) monitoring in UK children at risk of hypertension takes place predominantly in secondary and tertiary care. Objectives To investigate (i) the availability of paediatric BP equipment in primary care (PC) and (ii) the confidence of PC professionals in measuring and interpreting childrens BP. Methods 103 PC practices were approached to complete a questionnaire. BP equipment availability and confidence with BP measurement and interpretation were recorded (interval scale 1–10). Cuff size and equipment type were documented. Results 95 (92%) practices responded; 40/95 possessed paediatric BP cuffs. 35/51 devices were validated for paediatric use. Median (IQR) confidence in BP measurement was 7 (2–8). Confidence in BP interpretation was 3 (2–6), though this improved if normal ranges were provided (8 (6–9), p<0.01). Conclusions Investment in appropriate equipment and education is required to allow PC to successfully monitor BP in children.

Urinary VCAM-1 as a biomarker of lupus nephritis disease activity

Up to 80% of children with Juvenile Systemic Lupus Erythematosus (JSLE) develop lupus nephritis (LN) (1), with the 5-year renal survival rate varying between 44-94% (2-4). Conventional markers of JSLE disease activity fail to adequately predict impending LN flares (5), with significant renal involvement (class III, IV or V LN) known to occur with low level proteinuria (6). Cross-sectional adult SLE studies have shown urinary vascular cell adhesion molecule-1 (VCAM-1) to be significantly higher in active LN than inactive LN or healthy controls, correlating with traditional markers of LN disease activity (7, 8).

PReS-FINAL-2290: Is an abnormal lipid profile at diagnosis related to increased disease activity in JSLE patients

Lipid profile has been studied in Systemic Lupus Erythematous (SLE) due to the significant morbidity and mortality associated with premature coronary heart disease. Variations in lipid profile in adults with SLE are associated with overall disease activity, with Triglyceride (TG) levels associated with renal flare. Examination of lipid profile in juvenile-onset SLE (JSLE) showed a statistically significant drop in TG in transition from a state of active disease to inactive disease & TG levels to be significantly correlated with proteinuria at diagnosis.

PReS-FINAL-2303: Exploring potential differences in demographics, family history and disease characteristics in JSLE patients with different age of onset

Juvenile-onset SLE (JSLE) is a severe auto-immune disease that can occur in children at any age. Variations regarding the extent of organ involvement, disease activity and damage are found in different age categories. Factors that may contribute to an earlier age of onset are gender, ethnicity and positive family history of SLE. It has been shown that JSLE has a more aggressive disease course compared to adult onset SLE. Correspondingly, it seems that disease severity in younger JSLE patients increases with decreasing age 1,2,4. However, there is some conflicting evidence.

P03 Novel Urine Biomarkers For Monitoring Disease Activity in Juvenile Lupus Nephritis: A Prospective Longitudinal Validation Study

Background Systemic Lupus Erythematosus (JSLE) is a severe autoimmune condition with lupus nephritis (LN) seen more frequently in juvenile disease where up to 80% have renal involvement [1]. The renal biopsy is crucial for diagnosis and classification but has a limited role in monitoring. Current methods of monitoring renal disease activity over time rely on a variety of standard laboratory markers and the use of disease activity tools such as the British Isles Lupus Assessment Group index score (BILAG). Improving methods of monitoring and predicting disease activity may improve the long-term renal outcome. Aims and methods This prospective longitudinal study aimed to identify whether standard and/or novel biomarkers are useful for monitoring and predicting LN disease activity. Using patients recruited to the UK JSLE study, urine and blood samples were collected during routine clinical reviews. The study had full ethical approval. Results The JSLE cohort (n = 64), seen at 3 (interquartile range IQR: 2–5) clinical reviews over 364 (182–532) days were aged 14.1 (11.8–15.8) years and 80% female. Active renal episodes (23% total; renal BILAG A/B) had significantly increased concentration of; monocyte chemoattractant protein 1 (MCP1), neutrophil gelatinase associated lipocalin (NGAL), erythrocyte sedimentation rate, anti-double stranded DNA, urine albumin:creatinine ratio (UACR), creatinine, and reduced complement 3 (C3), C4 and lymphocytes. Cross sectional multivariate analysis demonstrated MCP1 and C3 as independent variables (p < 0.001) for active renal disease. Longitudinally, MCP1 was an excellent predictor of improved renal disease (area under the curve AUC: 0.81; p = 0.013; concentration 343pg/ml, specificity 71%, sensitivity 70%); NGAL was a good predictor of worsened renal disease activity (AUC 0.76; p = 0.04; concentration 30ng/ml, specificity 60%, sensitivity 61%). Standard markers could not predict disease activity changes. Conclusion Novel biomarkers (MCP1, NGAL) are able to predict changes in JSLE related renal disease activity. Biomarker-led monitoring may facilitate earlier intervention to prevent renal damage. The development of point of care biomarker testing is now in progress. Reference Watson L, Leone V, Pilkington C, Tullus K, Rangaraj S, McDonagh JE, Gardner-Medwin J, Wilkinson N, Riley P, Tizard J et al. Arthritis Rheum 2012.