Eve Smith

The child with a limp: a symptom and not a diagnosis

The limping child frequently poses a diagnostic challenge and clinical assessment may not be easy. Epidemiological studies are sparse; in one study1 children with an acute limp accounted for <2% of all paediatric emergency department (ED) attendances although the frequency may well be different in the primary care setting. Trauma is the commonest cause of limping and many cases of atraumatic limp will resolve spontaneously. However, limp is not a diagnosis and it is important to assess limping children carefully as rarer, but serious, causes can be associated with significant morbidity, and even mortality, if there is a delay in diagnosis. Children warranting urgent investigation are the very young (<3 years of age), the ill and febrile, the non-weight bearing and those with painful restricted hip movements. Teaching on the limping child correctly focuses on the hip, where significant pathology often occurs. However, limp may be due to extra-articular causes or joint problems other than those affecting the hip; these can be easily missed without careful assessment. In most cases, acute limping describes an antalgic (painful) gait, that is, minimising weight bearing on a sore limb, with a shortened stance phase and increased swing phase of the gait cycle. Acute refers to duration of 1–2 days in contrast to a chronic limp (>6 weeks) and subacute (2 days and up to 6 weeks). Subtle limping may be accentuated by asking the child to run: listening for an asymmetric cadence can be helpful. Limping is also used to describe other abnormal gait patterns, often due to a spectrum of causes that are not acute in origin (eg, cerebral palsy) and not covered in detail in this article. The age of the child is helpful in establishing a differential diagnosis (table 1)2 ,3 which will be aided by careful initial assessment, judicious use …

The development and assessment of biological treatments for children

The development of biological agents with specific immunological targets has revolutionized the treatment of a wide variety of paediatric diseases where traditional immunosuppressive agents have been partly ineffective or intolerable. The increasing requirement for pharmaceutical companies to undertake paediatric studies has provided impetus for studies of biologics in children. The assessment of biological agents in children to date has largely relied upon randomized controlled trials using a withdrawal design, rather than a parallel study design. This approach has been largely used due to ethical concerns, including use of placebo treatments in children with active chronic disease, and justified on the basis that treatments have usually already undergone robust assessment in related adult conditions. However, this study design limits the reliability of the data and can confuse the interpretation of safety results. Careful ongoing monitoring of safety and efficacy in real-world practice through national and international biologics registries and robust reporting systems is crucial. The most commonly used biological agents in children target tumour necrosis factor-α, interleukin-1, interleukin-6 and cytotoxic lymphocyte-associated antigen-4. These agents are most frequently used in paediatric rheumatic diseases. This review discusses the development and assessment of biologics within paediatric rheumatology with reference to the lessons learned from use in other subspecialties.

Urinary biomarkers in childhood lupus nephritis.

Juvenile-onset systemic lupus erythematosus (JSLE) is a rare, severe multisystem autoimmune disease affecting the kidney (Lupus Nephritis, LN) in up to 80% of children. LN is more severe in children than adults, with potential for irreversible kidney damage requiring dialysis or transplant. Renal biopsy is currently the gold standard for diagnosing and monitoring LN, however, it is invasive and associated with complications. Urine biomarkers have been shown to be better than serum biomarkers in differentiating renal disease from other organ manifestations. Over the past decade, there have been an increasing number of studies investigating specific candidate biomarkers implicated in the pathogenesis of LN or screening for urinary biomarkers using hypothesis free methods. In this review, developments in urine biomarkers for LN will be reviewed, highlighting those that are of relevance to children and have gone through validation in independent international patient cohorts, bringing them close to clinical translation.

Increased concentration of plasma TNFR1 and TNFR2 in paediatric lupus nephritis

Background Juvenile-onset systemic lupus erythematous (JSLE) is a debilitating condition that frequently involves the kidneys (lupus nephritis; LN). Tumour necrosis factor alpha (TNF-α), an important pro-inflammatory cytokine, is expressed locally in the kidney and correlates with LN disease activity. The aim of this study was to ascertain whether soluble receptors for TNF-α (sTNFR1/sTNFR2) are significantly increased in children with LN. Methods Plasma samples were collected from JSLE patients at routine review. Concentrations of sTNFR1 and sTNFR2 were measured (median; interquartile range, IQR) using enzyme-linked immunosorbent assay (ELISA) in 25 JSLE patients (seven LN) and 20 healthy controls (HCs). Results sTNFR2 concentration was significantly increased in JSLE (5149 pg/dl, 3413–8561) compared to HCs (3858 pg/dl, 2254–5165; p = 0.049). sTNFR1 concentration was significantly increased in active LN (n = 7, 1765 pg/dl, IQR 1133–4167) compared to inactive LN (n = 18, 1104 pg/dl, 886–1272; p = 0.018). There was a non-significant increase in sTNFR2 concentration in active LN (9829 pg/dl, 3298–21271) compared to inactive LN (4595 pg/dl, 3345–6993; p = 0.146). sTNFR1 concentration correlated moderately with sTNFR2 (r = 0.66, p < 0.001). sTNFR2 demonstrated strong positive correlations with ESR (r = 0.941, p < 0.01) and anti-dsDNA antibodies (r = 0.998, p = 0.041). Both receptors also positively correlated with creatinine (TNFR1 r = 0.81, p < 0.001; TNFR2 r = 0.50, p = 0.015) and urinary albumin creatinine ratio (TNFR1 r = 0.64, p < 0.01; TNFR2 r = 0.63, p < 0.01). Conclusions These data indicate that sTNFR1 and sTNFR2 concentrations are elevated in LN and may reflect renal activity. These results provide basis for further investigation into the pathological pathways underlying LN.

Predictors of access to care in juvenile systemic lupus erythematosus: evidence from the UK JSLE Cohort Study

OBJECTIVE The objective of this study was to investigate factors that may influence the interval between symptom onset and JSLE diagnosis. METHODS Data from all patients recruited to the UK JSLE Cohort Study between 2006 and 2011 and meeting ACR criteria for lupus were analysed. Variables associated with time between symptom onset and diagnosis were identified using correlation tests. Linear regression was used to identify independent predictors of access to care. RESULTS Two hundred and fifty-seven children with JSLE were included in the analysis (216 females, 41 males, ratio 5.3:1). The median time from symptom onset to diagnosis was 0.4 years (range 0.0-14.1 years, interquartile range 0.2-1.4). A linear regression model identified being of African or Caribbean origin (P = 0.006), Asian (P = 0.045), referred by a paediatrician (P = 0.047) or having nephritis (P = 0.045) at presentation as independent predictors of shorter time to diagnosis. Being of Caribbean or Asian origin, compared with white, was associated with a 56% and 37% reduction in geometric mean time to diagnosis, respectively. Similarly, being referred to paediatric rheumatology by a paediatrician or having nephritis at presentation was also associated with a 32% and 36% reduction in geometric mean time to diagnosis, respectively. CONCLUSION Within this national UK cohort, ethnic origin, initial source of referral and having lupus nephritis at presentation were strong predictors of the interval to establishing a diagnosis of JSLE.

Fifteen-minute consultation: A structured approach to the management of hypermobility in a child

Objective To present a structured approach for an outpatient consultation of a child with hypermobility. Method Review of the literature and a description of the approach commonly adopted in a paediatric out-patient setting. Conclusions A focused history and examination is the key to reaching an appropriate differential diagnosis and planning management for children with hypermobility. Case A 10-year-old child is referred to your general paediatric clinic with frequent ‘cracking and clicking’ of her joints and a history of intermittent aches and pains over the last 6 months.

THU0373 Demonstration of an “Excellent” Biomarker Panel for Identifying Active Lupus Nephritis in Children

Background Lupus nephritis (LN) is a serious manifestation of Juvenile-onset Systemic Lupus Erythematosus (JSLE), affecting up to 80% of patients [1]. Conventional markers of JSLE disease activity fail to adequately predict impending LN flares. Renal histology is the gold standard for diagnosing and predicting renal prognosis in LN, and is rarely repeated for monitoring purposes due to its invasive nature. Single novel urine biomarkers are good at predicting and detecting LN flares [2], but to date, no individual urine biomarkers have achieved an “excellent” predictive value (area under the curve (AUC) >0.9). Objectives To assess if combining novel and traditional biomarkers can result in an excellent biomarker panel for identifying active LN. Methods Participants of the UK JSLE cohort study were aged less than 16 years at the time of diagnosis. Disease activity data was collected using the paediatric British Isles Lupus Assessment Group (pBILAG2004) score. Patients were cross-sectionally categorised as active LN (pBILAG2004 renal domain score A or B plus previous histological confirmation of LN), in-active LN (pBILAG2004 renal domain score D or E) or healthy controls (HCs). Novel urinary biomarkers; vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein 1 (MCP-1), lipocalin like prostaglandin D synthase (LPGDS), transferrin, ceruloplasmin and alpha-1-acid glycoprotein (AGP) were quantified by enzyme-linked immunosorbent assays. Neutrophil gelatinase associated lipocalin (NGAL) was measured using the Abbot Architect assay. Binary logistic regression modeling and receiver-operating curve (ROC curve) analysis assessed combinations of novel and traditional biomarkers. The study had full ethical approval in place. Results 61 JSLE patients and 19 HCs were recruited. 15 (25%) JSLE patients had active LN and 46 (75%) had in-active LN. Urinary AGP, ceruloplasmin, VCAM-1, MCP-1, LPGDS and transferrin levels were significantly increased in active LN (all p≤0.01). Urinary NGAL levels did not differ between patient groups (p=0.245). AGP was the best single biomarker differentiating active and inactive LN (good AUC 0.890, p≤0.001). Combining novel biomarkers improved the identification of active LN (optimal combination; AGP, ceruloplasmin, LPGDS, transferrin, excellent AUC 0.923, p<0.001). Additional improvement was seen with the addition of dsDNA to this combination (excellent AUC 0.933, p≤0.001). Conclusions A combination of novel urinary and traditional biomarkers produces an excellent “biomarker panel” for active LN identification on a cross sectional basis. It is anticipated that biomarker led monitoring will improve long-term renal outcomes in JSLE patients in the future. References Watson L, Leone V, Pilkington C, et al. Disease activity, severity, and damage in the UK Juvenile-Onset Systemic Lupus Erythematosus Cohort. Arth Rheum 2012;64(7):2356-65. Watson L, Tullus K, Pilkington C, et al. Urine biomarkers for monitoring juvenile lupus nephritis: a prospective longitudinal study. Ped Nephrol 2013;29(3):397-405. Disclosure of Interest None declared

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).

Clinical predictors of active LN development in children – evidence from the UK JSLE Cohort Study

Background Juvenile-onset systemic lupus erythematosus (JSLE) patients may develop lupus nephritis (LN) during their initial presentation, or later in their disease. This study aimed to assess whether clinical/demographic factors characterize patients with LN within the United Kingdom JSLE Cohort Study, and whether such factors predict subsequent LN development. Methods Univariate logistic regression modelling compared clinical/demographic factors in patients with and without LN at baseline. For those who subsequently developed LN, Cox proportional-hazard modelling was used to test the association between such factors and time to LN development. Covariates with p < 0.2 univariately were included within a multiple-regression model. Results A total of 121/331 (37%) patients presented with active LN at baseline, with first American College of Rheumatology (ACR) score (p < 2.0 × 10–16), severe hypertension (p = 0.0006), proteinuria (p < 2.0 × 10–16), creatinine (p = 1.0 × 10–16), erythrocyte sedimentation rate (p = 1.0 × 10–16), neutrophils (p < 2.0 × 10–16), complement 3 (C3) (p = 4.0 × 10–16) and ethnicity (p = 3.0 × 10–13) differing between those with and without LN. Of the 210 individuals without active LN at baseline, 13 patients had a single visit and were excluded from further analysis. Thirty-four of 197 (17%) developed LN after a median of 2.04 years (interquartile range, 0.8–3.7), with higher ACR scores (p = 0.014, hazard ratio (HR) = 1.45, 95% confidence interval (CI) = 1.08–1.95) and lower C3 levels (p = 0.0082, HR = 0.27, 95% CI = 0.10–0.68) demonstrated as predictors of subsequent LN. Conclusions Clinical and demographic factors can help to characterize patients at increased risk of LN.

Growing international evidence for urinary biomarker panels identifying lupus nephritis in children – verification within the South African Paediatric Lupus Cohort

Background A urinary biomarker panel including alpha-1-acid-glycoprotein (AGP), lipocalin-like-prostaglandin-D-synthase (LPGDS), transferrin and ceruloplasmin demonstrates an ‘excellent’ ability for identifying active lupus nephritis in UK/US children. This study aimed to assess whether this panel identifies active lupus nephritis within the South African Paediatric Lupus Cohort. Methods Juvenile-onset-systemic lupus erythematosus (JSLE) patients aged < 19 years at diagnosis and healthy controls were recruited. Patients were categorized as having active lupus nephritis (renal BILAG score; A/B and previous histological confirmation) or inactive lupus nephritis (renal BILAG score: D/E). Urinary biomarkers were quantified by ELISA. Mann–Whitney U-test compared biomarker levels between groups. Binary logistic regression and receiver operating curve analysis assessed biomarker combinations. Results Twenty-three juvenile-onset-systemic lupus erythematosus patients were recruited with a median age of 13.5 years (interquartile range (IQR) 12.7–14.9) and disease duration of 2.6 years (IQR 1.8–4.0). Eighteen healthy controls had a median age of 11.0 years (IQR 10.0–12.0). AGP, LPGDS, transferrin, ceruloplasmin and VCAM-1 were significantly higher in active than in inactive lupus nephritis patients (corrected p-values, all pc < 0.05), with no difference between inactive lupus nephritis patients and healthy controls (all pc = 1.0). The optimal biomarker combination included AGP, ceruloplasmin, LPGDS and transferrin (area under the curve = 1.0). Conclusions A urinary biomarker panel comprising AGP, ceruloplasmin, LPGDS and transferrin previously validated within UK/US cohorts also performed excellently within a racially distinct South African cohort which displayed more severe lupus nephritis.