Clinical and laboratory characteristics in juvenile-onset systemic lupus erythematosus across age groups.

BACKGROUND: Systemic lupus erythematous (SLE) is a systemic autoimmune/inflammatory condition. Approximately 15-20% of patients develop symptoms before their 18th birthday and are diagnosed with juvenile-onset SLE (JSLE). Gender distribution, clinical presentation, disease courses and outcomes vary significantly between JSLE patients and individuals with adult-onset SLE. This study aimed to identify age-specific clinical and/or serological patterns in JSLE patients enrolled to the UK JSLE Cohort Study. METHODS: Patient records were accessed and grouped based on age at disease-onset: pre-pubertal (≤7 years), peri-pubertal (8-13 years) and adolescent (14-18 years). The presence of American College of Rheumatology (ACR) classification criteria, laboratory results, disease activity [British Isles Lupus Assessment Group (BILAG) and Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2 K) scores] and damage [Systemic Lupus International Collaborating Clinics (SLICC) damage index] were evaluated at diagnosis and last follow up. RESULTS: A total of 418 JSLE patients were included in this study: 43 (10.3%) with pre-pubertal disease onset; 240 (57.4%) with peri-pubertal onset and 135 (32.3%) were diagnosed during adolescence. At diagnosis, adolescent JSLE patients presented with a higher number of ACR criteria when compared with pre-pubertal and peri-pubertal patients [pBILAG2004 scores: 9(4-20] vs. 7(3-13] vs. 7(3-14], respectively, p = 0.015] with increased activity in the following BILAG domains: mucocutaneous (p = 0.025), musculoskeletal (p = 0.029), renal (p = 0.027) and cardiorespiratory (p = 0.001). Furthermore, adolescent JSLE patients were more frequently ANA-positive (p = 0.034) and exhibited higher anti-dsDNA titres (p = 0.001). Pre-pubertal individuals less frequently presented with leukopenia (p = 0.002), thrombocytopenia (p = 0.004) or low complement (p = 0.002) when compared with other age groups. No differences were identified in disease activity (pBILAG2004 score), damage (SLICC damage index) and the number of ACR criteria fulfilled at last follow up. CONCLUSIONS: Disease presentations and laboratory findings vary significantly between age groups within a national cohort of JSLE patients. Patients diagnosed during adolescence exhibit greater disease activity and "classic" autoantibody, immune cell and complement patterns when compared with younger patients. This supports the hypothesis that pathomechanisms may vary between patient age groups.

Outcomes following mycophenolate mofetil versus cyclophosphamide induction treatment for proliferative juvenile-onset lupus nephritis.

BACKGROUND: Juvenile-onset systemic lupus erythematosus (JSLE) is more severe than adult-onset disease, including more lupus nephritis (LN). Despite differences in phenotype/pathogenesis, treatment is based upon adult trials. This study aimed to compare treatment response, damage accrual, time to inactive LN and subsequent flare, in JSLE LN patients treated with mycophenolate mofetil (MMF) versus intravenous cyclophosphamide (IVCYC). METHODS: UK JSLE Cohort Study participants, ≤16 years at diagnosis, with ≥4 American College of Rheumatology criteria for SLE, with class III or IV LN, were eligible. Mann-Whitney U tests, Fisher's exact test and Chi-squared tests were utilized for statistical analysis. RESULTS: Of the patients, 34/51 (67%) received MMF, and 17/51 (33%) received IVCYC. No significant differences were identified at 4-8 and 10-14 months post-renal biopsy and last follow-up, in terms of renal British Isles Lupus Assessment Grade scores, urine albumin/creatinine ratio, serum creatinine, ESR, anti-dsDNA antibody, C3 levels and patient/physician global scores. Standardized Damage Index scores did not differ between groups at 13 months or at last follow-up. Inactive LN was attained 262 (141-390) days after MMF treatment, and 151 (117-305) days following IVCYC ( p = 0.17). Time to renal flare was 451 (157-1266) days for MMF, and 343 (198-635) days for IVCYC ( p = 0.47). CONCLUSION: This is the largest study to date investigating induction treatments for proliferative LN in children, demonstrating comparability of MMF and IVCYC.

Evaluation of the ACR and SLICC classification criteria in juvenile-onset systemic lupus erythematosus: a longitudinal analysis.

Objectives The Systemic Lupus International Collaborating Clinics (SLICC) group proposed revised classification criteria for systemic lupus erythematosus (SLICC-2012 criteria). This study aimed to compare these criteria with the well-established American College of Rheumatology classification criteria (ACR-1997 criteria) in a national cohort of juvenile-onset systemic lupus erythematosus (JSLE) patients and evaluate how patients' classification criteria evolved over time. Methods Data from patients in the UK JSLE Cohort Study with a senior clinician diagnosis of probable evolving, or definite JSLE, were analyzed. Patients were assessed using both classification criteria within 1 year of diagnosis and at latest follow up (following a minimum 12-month follow-up period). Results A total of 226 patients were included. The SLICC-2012 was more sensitive than ACR-1997 at diagnosis (92.9% versus 84.1% p < 0.001) and after follow up (100% versus 92.0% p < 0.001). Most patients meeting the SLICC-2012 criteria and not the ACR-1997 met more than one additional criterion on the SLICC-2012. Conclusions The SLICC-2012 was better able to classify patients with JSLE than the ACR-1997 and did so at an earlier stage in their disease course. SLICC-2012 should be considered for classification of JSLE patients in observational studies and clinical trial eligibility.

A survey of foot problems in juvenile idiopathic arthritis.

BACKGROUND: Evidence suggests that foot problems are common in juvenile idiopathic arthritis (JIA), with prevalence estimates over 90%. The aim of this survey was to describe foot-related impairment and disability associated with JIA and foot-care provision in patients managed under modern treatment paradigms, including disease-modifying anti-rheumatic drugs (DMARDs) and biologic therapies. METHODS: The Juvenile Arthritis Foot Disability Index (JAFI), Child Health Assessment Questionnaire (CHAQ), and pain visual analogue scale (VAS) were recorded in 30 consecutive established JIA patients attending routine outpatient clinics. Foot deformity score, active/limited joint counts, walking speed, double-support time (s) (DS) and step length symmetry index % (SI) were also measured. Foot-care provision in the preceding 12 months was determined from medical records. RESULTS: Sixty-three per cent of children reported some foot impairment, with a median (range) JAFI subscale score of 1 (0-3); 53% reported foot-related activity limitation, with a JAFI subscale score of 1 (0-4); and 60% reported participation restriction, with a JAFI subscale score of 1 (0-3). Other reported variables were CHAQ 0.38 (0-2), VAS pain 22 (0-79), foot deformity 6 (0-20), active joints 0 (0-7), limited joints 0 (0-31), walking speed 1.09 m/s (0.84-1.38 m/s), DS 0.22 s (0.08-0.26 s) and SI +/-4.0% (+/-0.2-+/-31.0%). A total of 23/30 medical records were reviewed and 15/23 children had received DMARDS, 8/23 biologic agents and 20/23 multiple intra-articular corticosteroid injections. Ten children received specialist podiatry care comprising footwear advice, orthotic therapy and silicone digital splints together with intrinsic muscle strengthening exercises. CONCLUSION: Despite frequent use of DMARD/biologic therapy and specialist podiatry-led foot care, foot-related impairment and disability persists in some children with JIA.

Inflammatory cytokines in juvenile idiopathic arthritis: effects on physical growth and the insulin-like-growth factor axis.

OBJECTIVE: To investigate the relationship between markers of inflammation with physical growth and systemic markers of GH secretion in JIA. DESIGN: This is a cross sectional prospective study of patients with JIA recruited during therapeutic arthrocentesis of 17 children with JIA (F,10): 8 oligoarticular (OJIA) and 9 polyarticular (PJIA). RESULTS: Median adjusted height (AHt) SDS was -0.3 (-2.2 to 1.6). Serum ALS SDS (median -1.3, range -2.7 to -0.6) was reduced compared with serum IGFBP-3 SDS (median -0.5, range -7.7 to 2.3) and IGF-1 SDS (median -0.2, range -0.5 to 0.5). Log serum IL5 (95% CI -3.25, -0.81) and log serum IL15 (95% CI -9.58, -4.10) were independent factors associated with AHt SDS. Inflammatory cytokines individually showed no association with IGF-1, IGFBP-1, -2, -3 and ALS. CONCLUSION: Children with JIA and mild degree of growth retardation show decreased ALS and IGFBP-3. Cytokines did not show an association to systemic markers of GH secretion. However, this study reports the novel, preliminary association between serum levels of IL5 and IL15 and the extent of short stature.

Association between duration of symptoms and severity of disease at first presentation to paediatric rheumatology: results from the Childhood Arthritis Prospective Study.

OBJECTIVES: To study the association between disease severity at first presentation to paediatric rheumatology (PRh) and length of time since symptom onset in children recruited to the Childhood Arthritis Prospective Study. METHODS: Children or=2 weeks were recruited from five UK hospitals. Data including demographics, disease features, Childhood Health Assessment Questionnaire (CHAQ), physician and parent global assessment and blood tests were collected at the first appointment with PRh (baseline). The association between symptom duration (defined as time from first reported symptom onset to presentation at PRh) and baseline disease characteristics was evaluated using non-parametric descriptive statistics and multivariable logistic regression analyses. RESULTS: Five hundred and seven children (65% female) were included: median age at onset was 6.8 yrs. Two hundred and thirty-three had oligoarthritis, 68 had RF-negative polyarthritis, 27 had systemic onset arthritis and 29 had arthritis that was not JIA. The median symptom duration was 4.6 months. Median symptom duration was shortest for children presenting with systemic arthritis (1.6 months) and longest for those with PsA (8.6 months). Children with a longer duration of symptoms were older and had higher median active joint counts but lower median ESR. Symptom duration did not correlate with CHAQ score at presentation. CONCLUSIONS: Children who have systemic arthritis had the shortest delay to PRh presumably because they are profoundly unwell. Children with joint pain/stiffness but normal ESR had longer delays suggesting that if blood tests do not indicate inflammation, the diagnosis of JIA may be overlooked.

Costing juvenile idiopathic arthritis: examining patient-based costs during the first year after diagnosis.

OBJECTIVES: There are few data on the treatment patterns and associated cost of treating children with inflammatory arthritis including juvenile idiopathic arthritis (JIA), in the short or long term. The aim of this study was to obtain patient-based costs for treating children with JIA in the UK, in the first year from diagnosis and from the secondary health care payer perspective. METHODS: The Childhood Arthritis Prospective Study (CAPS) is an ongoing longitudinal study recruiting children with inflammatory arthritis from four UK hospital centres. Included children are newly diagnosed,

Cytokine profiling and in vitro studies of murine bone growth using biological fluids from children with juvenile idiopathic arthritis.

OBJECTIVE: Growth retardation in children with chronic inflammatory disease may be partly due to direct effects of pro-inflammatory cytokines on the growth plate and requires further investigation. DESIGN: This study assessed the cytokine concentrations in serum and synovial fluid (SF) in juvenile idiopathic arthritis (JIA), and determined the effect of the biological fluid on cultured murine metatarsal growth. PATIENTS: Serum and SF were obtained from four children attending for arthrocentesis (child A, systemic; children B, C and D, oligoarticular). In addition, serum samples were obtained from four more children (children E and F, polyarticular; child G, oligoarticular). MEASUREMENTS: Anthropometry, cytokine levels and longitudinal bone growth were assessed. RESULTS: Cytokines were elevated to a variable extent in the samples. Although all serum samples were associated with reduced metatarsal growth, only SF from child A and child B reduced metatarsal growth. Metatarsals treated with child A's SF showed reduced proliferation, reduced proliferative and mineralizing zone width, and increased hypertrophic zone width. Tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 concentrations were elevated in child A's SF. However, SF exposure with neutralizing antibodies to these cytokines or IGF-1 did not improve metatarsal growth. CONCLUSION: SF and serum JIA samples can impair bone growth at the growth plate. In synovial fluid, the effect is variable but resistant to treatment with IL-1beta, IL-6 and TNF-alpha specific antibodies and IGF-1, suggesting that other factors in this biological fluid may also have an effect on longitudinal growth through IGF-1-independent mechanisms.

Impaired endothelial function in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) patients suffer from excess cardiac deaths due to accelerated atherosclerosis. Endothelial dysfunction is a marker of early atherosclerosis. We tested the hypothesis that SLE patients have impaired endothelial function and assessed the relationship between endothelial function and clinical outcome over the subsequent five years. Thirty-six female SLE patients were compared with 22 healthy age and sex matched controls. Endothelial dependent vasodilatation (EDD) was assessed at the brachial artery in response to shear stress. Endothelium-independent dilatation induced by glyceryl trinitrate was also measured. Patients were followed for up to five years and the development of damage in the cardiovascular and other systems recorded. SLE patients showed significantly impaired endothelial function (median EDD 5.6%, IQR 3.1-7.2%) compared with healthy controls (median EDD 8.0%, IQR 6.3-9.3%; P = 0.001). Endothelium independent dilatation did not differ between the two groups. Endothelial function was significantly worse in postmenopausal compared with premenopausal women (median EDD 6.6%, IQR 3.9-7.8% versus 3.1%, IQR 2.6-5.1%; P = 0.016). Total cholesterol was inversely correlated with endothelial function in SLE patients (Spearman correlation r = -0.422, P = 0.025). There was no relationship between endothelial function and the development of damage in any organ system, including the cardiovascular system during patient follow-up. Patients with SLE have impaired endothelial Lupus (2007) 16, 84-88.

Biologic therapies for juvenile arthritis.

A group of therapies with exciting potential has emerged for children and young people with severe juvenile idiopathic arthritis (JIA) uncontrolled by conventional disease modifying drugs. Theoretical understanding from molecular biologic research has identified specific targets within pathophysiological pathways that control rheumatoid arthritis (RA) and JIA. This review identifies the pathways of autoimmunity to begin to show how biologic agents have been produced to replicate, mimic, or block culpable molecules and so promote or inhibit cellular activity or proliferation. Of these agents, cytokine antagonists have shown greatest promise, and early clinical studies of tumour necrosis factor (TNF) blockade have identified dramatic clinical benefit in many children with JIA. However, as will also be discussed, overlap of pathways within a complex immune system makes clinical response unpredictable and raises additional ethical and administrative concerns.

Diffuse endothelial dysfunction is common to ANCA associated systemic vasculitis and polyarteritis nodosa.

BACKGROUND: Excess cardiovascular mortality complicates systemic rheumatic disease, suggesting an accelerated atheromatous process, which it has been proposed relates to the vascular inflammation common in such diseases. Impaired endothelium dependent vasodilatation is an early marker of atheromatous disease. It has previously been shown that such endothelial cell dysfunction (ECD) occurring in the brachial artery can complicate primary systemic necrotising vasculitis (SNV). OBJECTIVE: To determine if ECD occurs in a wider spectrum of primary SNV, if it is restricted to the major arteries, and whether vasculitis subgroup, ANCA status, or renal involvement influenced the endothelial responses. METHODS: Fifty four patients attending the Birmingham vasculitis clinic, including patients with a range of ANCA and non-ANCA associated primary vasculitides, and a group of age matched controls were recruited. The length of patient follow up and disease activity was variable. Disease activity, damage scores, and cardiovascular risk factors were recorded before assessment of flow mediated brachial artery vasodilatation by high resolution ultrasound. Dermal microvascular responses to acetylcholine were also measured in 32 patients and 21 controls by laser Doppler flowmetry. RESULTS: ECD was demonstrated in all primary SNV subgroups of patients with ANCA associated vasculitis and in polyarteritis nodosa, compared with controls. Significant impairment occurred in both vascular beds, regardless of vessel size targeted in the inflammatory vasculitis, ANCA association and titre, or renal involvement. CONCLUSIONS: Diffuse endothelial dysfunction, a predictor of atherosclerotic disease, is found extensively in primary systemic vasculitis. Involvement of different vascular beds is independent of target vessel size or ANCA association, and is unrelated to local disease expression. It is suggested that this results from a systemic response that may be a consequence of primary vasculitis, but is distinct from the local inflammatory vasculitic process.

Seasonal differences in finger skin temperature and microvascular blood flow in healthy men and women are exaggerated in women with primary Raynaud's phenomenon.

AIMS: Patients with primary Raynaud's phenomenon (PRP) have more severe symptoms in the winter. The aetiology of this is more complex than simply increased vasoconstriction in response to the immediate ambient temperature. The aim of this study was to investigate differences in skin temperature (Tsk), microvascular blood flow and responses to endothelium-dependent and independent vasodilators in healthy controls, and women with PRP under identical environmental temperatures but in different seasons. METHODS: Ten women with PRP were compared with age matched women (10) and men (10). Finger skin responses were recorded immediately on arrival, after stabilizing in a temperature regulated laboratory at 22-24 degrees C, and at matched warm (35 degrees C) and cold (15 degrees C) Tsk in the winter and summer. Baseline red blood cell flux (r.b.c. flux), and the change in flux in response to iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP) were recorded by laser Doppler fluxmetry at the warm and cold Tsk. RESULTS: Arrival Tsk were significantly cooler for all subjects during the winter (mean seasonal difference -2.6 degrees C, P < 0.0001), and markedly colder in subjects with PRP (mean seasonal difference -3.5 degrees C, P < 0.0005). Statistically significant seasonal differences persisted in all subjects at stable Tsk despite an identical laboratory temperature (mean difference 1.3 degrees C, P < 0.0001). To achieve comparable controlled finger Tsk a significantly colder local environment was required for male controls (mean of -2.1 degrees C, P < 0.0001), and a significantly warmer environment for subjects with PRP (mean of + 2.4 degrees C, P < 0.0001) compared with female controls. This needed to be warmer in the winter, by a mean of 2.4 degrees C, than the summer for all subjects. Vasodilatation in response to ACh, but not SNP, was significantly smaller (P < 0.0001) in the PRP group compared with the female controls for all visits, with most of this difference arising in the winter visits (P < 0.01). CONCLUSIONS: There is a seasonal and persistent influence on finger Tsk, and microvascular blood flow in healthy men and women, which modifies the observed responses to immediate changes in finger Tsk. The seasonal differences are greater in women than men, and are further exaggerated in women with PRP, in whom this is associated with reduced endothelium-dependent vasodilatation.

Use of quantitative ultrasound to assess bone status in children with juvenile idiopathic arthritis: a pilot study.

Periarticular osteoporosis around inflammed joints and generalized osteoporosis have been shown to be markers of disease activity and severity in children with juvenile idiopathic arthritis (JIA). Bone mineral density (BMD) in adults can be assessed precisely by dual X-ray absorptiometry (DXA), but this technique has not been used widely in children. Quantitative ultrasound (QUS) may provide an alternative method for assessment of bone status. The aim of this pilot study was to compare QUS to DXA in assessing generalized osteoporosis in a cohort of patients JIA. Twenty-two Caucasian children (15 females, 7 males) with JIA of duration 19-142 months (mean 71 mo) and age 7-17 yr were recruited. Total body and lumbar spine BMD and bone mineral content (BMC) were measured by DXA using standard procedures on a Lunar DPX-L scanner. QUS was performed using Myriad SoundScan 2000. Speed of sound (SOS) was measured at the right midtibia. The DXA results were compared to QUS using linear regression analysis. Spine and total body BMD measured by DXA correlated significantly with tibia SOS (spine: r = 0.57, p < 0.007; total body: r = 0.68, p < 0.001). Spine BMC was similarly related to SOS as BMD (r = 0.58, p < 0.007). Individual patient weight and height were strong predictors of BMD, but only moderate predictors of SOS. The mean spine BMD was lower in the JIA patients compared to the normal ranges (mean Z-score of -1.19). BMD Z-scores were negatively associated with disease duration. Patients taking steroids were associated with lower Z-scores. In conclusion, SOS shows a significant correlation with BMD as measured by DXA, albeit with wide 95% confidence intervals in this small pilot study. QUS was also well tolerated and was technically easy to perform in these children. With the added advantage that it is free from radiation risk, further assessment of this potentially valuable tool for measuring bone status in children is warranted.

Haemodynamic effects of adrenomedullin in human resistance and capacitance vessels.

AIMS: The haemodynamic effects of adrenomedullin and calcitonin gene-related peptide (CGRP) were studied in resistance and capacitance vessels of healthy volunteers. METHODS: Adrenomedullin and CGRP were infused into the brachial artery of eight healthy subjects on two separate occasions at doses between 0.3-30 pmol min(-1). Forearm blood flow was measured using venous occlusion plethysmography. Venodilatation to adrenomedullin and CGRP was assessed in a further eight subjects by infusing the peptides at doses between 0.3-10 pmol min(-1) into a dorsal hand vein preconstricted with noradrenaline. Venodilator responses were measured as percentage reduction in noradrenaline preconstriction. RESULTS: Adrenomedullin and CGRP at a dose of 30 pmol min(-1), produced an increase in forearm blood flow of 288 +/- 42% and 252 +/- 30% respectively (mean +/- s.e. mean, P<0.001). At doses between 3 and 10 pmol min(-1) adrenomedullin was significantly more potent than CGRP. The vasodilatation to both peptides was of similar duration with a biological half-life of approximately 18 min. Adrenomedullin reversed constriction in dorsal hand veins by 84 +/- 2% (P<0.001) at a dose of 10 pmol min(-1). CGRP produced a similar effect reversing constriction by 72 +/- 12% at the same dose (P<0.01). In veins, adrenomedullin was also more potent than CGRP at doses between 0.3 and 3 pmol min(-1). CONCLUSIONS: The lowest dose of adrenomedullin producing significant arteriolar dilatation was calculated to produce plasma levels similar to those found in heart failure. These findings suggest that in pathophysiological conditions such as heart failure circulating levels of adrenomedullin may be within a range capable of influencing vascular resistance directly.

An investigation into variability in microvascular skin blood flow and the responses to transdermal delivery of acetylcholine at different sites in the forearm and hand.

AIMS: Transdermal iontophoresis in combination with laser Doppler fluxmetry (LDF) are useful techniques for examining dermal microcirculatory responses to different vasodilators. Differences in skin and microcirculation structure could influence the recorded baseline flux, and the observed vasodilatation. To examine this we compared baseline flux and the response of microvascular blood flow to a single vasodilator, acetylcholine, at sites in the forearm and hand. METHODS: Baseline microcirculation flow was recorded by LDF in a temperature controlled laboratory. The change in flux with iontophoresis of identical doses of acetylcholine, 150 microA for 40 s, was recorded at 12 different sites in the forearm and hand in 10 female and 3 male subjects. RESULTS: Baseline flux patterns and the vasodilatation to identical periods of iontophoresis of acetylcholine were site dependent. Palmar sites showed a higher baseline flux, but no vasodilatation to iontophoresis of acetylcholine. In contrast the volar forearm, dorsal hand and finger sites showed lower site-dependent baseline flux, but did vasodilate. CONCLUSIONS: Patterns of baseline flux are specific to sites on the hand and forearm reflecting differences in underlying microvascular structure. The vasodilatation to transdermal delivery of acetylcholine is also site dependent, but differences in skin structure may be more important than the underlying microvasculature in determining the response.

Correlation between CD29 density on CD8+ lymphocytes and serum IgG in systemic lupus erythematosus.

The purpose of this paper is to establish whether there is increased lymphocyte adhesion molecule density in systemic lupus erythematosus (SLE), which could alter the migration pathways and activation thresholds of lymphocytes and thus contribute to the pathogenesis of the disease. We analysed the CD11a, CD29 and CD2 bound antibody molecule (bam) density on the CD4+ and CD8+ CAMhigh (primed) lymphocytes of 28 SLE patients (8 active and 20 inactive by BILAG), using reproducible flow cytometric measurements, standardized with fluorescent beads and antibodies of known fluorescein: protein ratios. In a second patient cohort (17 patients), we investigated whether CD29 density on CD8+ cells correlated with measures of humoral (serum IgG) or cellular (urine neopterin) activation. In the first cohort, 36% of patients had elevated CD29 (beta 1 integrin) density on CD8+ cells. In the second cohort, CD29 density on CD8+ cells was found to be closely associated with total plasma IgG (r = 0.71, P = 0.001), but not with urine neopterin, disease activity (BILAG) or drug treatment. We conclude that CD29 on CD8+ cells is associated with B cell activation in SLE.