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4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent lung carcinogen present in tobacco products, and exposure to it is likely one of the factors contributing to the development of lung cancer in cigarette smokers. To exert its carcinogenic effects, NNK must be metabolically activated into highly reactive species generating a wide spectrum of DNA damage. We have identified a new class of DNA adducts, DNA-RNA cross-links found for the first time in NNK-treated mice lung DNA using our improved high-resolution accurate mass segmented full scan data-dependent neutral loss MS

Objectives Systemic Lupus Erythematosus (SLE) is a serious autoimmune disease often resulting in major end-organ damage and increased mortality. Currently, no data exists focussing on the presentation, long-term management and progression of SLE in the Australian paediatric population. We conducted the first Australian longitudinal review of childhood SLE, focussing on response to treatment and outcomes. Methods Detailed clinical and laboratory data of 42 children diagnosed with SLE before 16 years from 1998 to 2018 resident in Western Australia was collected. Data was collected at diagnosis and key clinical review time points and compared using the Systemic Lupus Collaborating Clinics (SLICC) and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) criteria. End organ damage was assessed against Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). Incidence rates of disease complications and end organ damage were determined. Results Of the 42 children, 88% were female with average age at diagnosis of 12.5 years. Indigenous Australians were over represented with an incidence rate 18-fold higher than non-Indigenous, although most children were Caucasian, reflecting the demographics of the Australian population. Median duration of follow-up was 4.25 years. On final review, 28.6% had developed cumulative organ damage as described by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (incidence rate: 0.08/PY (95% CI 0.04–0.14)), and one child died. Twenty-nine children had renal involvement (incidence rate: 0.38/PY (95% CI 0.26–0.56)). Of the 27 patients with biopsy proven lupus nephritis, 70% had Class III or IV disease. Average length of prednisolone use from diagnosis was 32.5 months. Hydroxychloroquine ( n = 36) and mycophenolate mofetil ( n =21) were the most widely used steroid sparing agents. 61.9% received rituximab and/or cyclophosphamide. Conclusion This is the first longitudinal retrospective review of Australian children with SLE, with a markedly higher incidence in Indigenous children. Although improving, rates of end organ complications remain high, similar to international cohort outcomes. Longitudinal multi-centre research is crucial to elucidate risk factors for poor outcomes, and identifying those warranting early more aggressive therapy.

AIM The incidence of Kawasaki disease (KD) is reported to be increasing in some populations. We sought to describe long-term trends in the incidence and epidemiology of KD in Australia over 25 years. METHODS Two nationally complete administrative datasets relevant to KD in Australia were analysed and compared. The Australian Red Cross Lifeblood Supply Tracking Analysis Reporting System (STARS) recorded all doses of immunoglobulin (IVIG) approved in Australia between January 2007 and June 2016. The Australian Institute of Health and Welfare National Hospital Morbidity Database (NHMD) records all episodes of care in hospitals across Australia. Data relevant to KD were extracted an analysed, with comparisons made for the period of data overlap. RESULTS During the period of data overlap (2007-2015) the IVIG treatment rate in the 0- to 4-year age group (calculated from STARS) was 14.31 per 100 000 person-years (95% confidence interval 13.67-14.97). The hospitalisation rate in the same age group (calculated from the NHMD) was 14.99 per 100 000 person-years (95% confidence interval 14.33-15.66). Hospitalisation rates rose at an average rate of 3.54% annually over the 25 years to 2017 in the 0- to 4-year age group, almost exclusively in the 1- to 4-year age group. CONCLUSIONS There is evidence of increasing KD diagnosis in Australia. Similar trends have also been reported in Asia but not in North America or Europe. Increasing diagnosis may reflect a true increase in disease incidence, increasing recognition or overdiagnosis. Further research is needed to determine the cause for these trends.

The safety and efficacy of elosulfase alfa were evaluated in a multicenter, open-label, phase 3b study in Australian Morquio A patients, consisting of a 49-week initial phase and an extension phase until elosulfase alfa was government funded. Thirteen patients (1-27 years) were enrolled. No new safety concerns were identified over 138 weeks. Most drug-related adverse events were mild or moderate in severity; none led to study discontinuation. After 49 weeks of treatment, median improvements from baseline were seen in the 6-minute walk test (+41.0 m), 3-minute stair climb test (+14.0 stairs/min), forced vital capacity (+16.4%), forced expiratory volume in 1 second (+14.1%), urine keratan sulfate (-7.1 µg/mg creatinine), and pain intensity. Growth, cardiac function, sleep, and quality of life results were mixed or stable. These results provide further evidence of the acceptable safety/tolerability profile of elosulfase alfa. The improvements in endurance, pulmonary function, and pain support findings from previous studies.

Objectives. To evaluate the demographic, disease activity, disability and health-related quality of life (HRQoL) differences between children with juvenile idiopathic arthritis (JIA) and their healthy peers, and between children with JIA with and without clinical temporomandibular joint (TMJ) involvement and its determinants. Methods. This study is based on a cross-sectional cohort of 3343 children with JIA and 3409 healthy peers, enrolled in the Pediatric Rheumatology International Trials Organisation (PRINTO) health-related quality of life (HRQoL) study or in the methotrexate trial. Potential determinants of TMJ involvement included demographic, disease activity, disability and HRQoL measures selected through univariate and multivariable logistic regression. Results. Clinical TMJ involvement was observed in 387/3343 (11.6%) JIA children. Children with TMJ involvement, compared to those without, more often had polyarticular disease course (95% versus 70%), higher Juvenile Arthritis Disease Activity Score (JADAS) (odds ratio (OR) 4.6), more disability and lower HRQoL. Children with TMJ involvement experienced clearly more disability and lower HRQoL compared to their healthy peers. The multivariable analysis, showed that cervical spine involvement (OR 4.6), disease duration > 4.4 years (OR 2.8), and having more disability (Childhood Health Assessment Questionnaire Disability Index >0.625) (OR 1.6) were the most important determinants for TMJ involvement. Conclusion. Clinical TMJ involvement in JIA is associated with higher disease activity, higher disability and impaired HRQoL. Our findings indicate the need for dedicated clinical and imaging evaluation of TMJ arthritis especially in children with cervical spine involvement, polyarticular course and longer disease duration. This article is protected by copyright. All rights reserved.

Autosomal recessive congenital ichthyosis is a genetically and phenotypically heterogenous group of scaling skin disorders. We describe a patient with ARCI caused by homozygous variants in NIPAL4, in whom the dermatologic phenotype and an associated arthropathy, markedly improved with ustekinumab.

Objective To describe the clinical features, management and outcome of 34 children with chronic recurrent multifocal osteomyelitis (CRMO) diagnosed at a single centre over 9 years. Methods All children identified with CRMO for the period 2005-13 were identified from a prospectively collected database, with additional data from hospital records. Results Thirty-four patients, 21 female and 13 male, were identified. The average age at symptom onset was 9.8 years (range 3.8-17.9) and at diagnosis was 10.9 years (range 5.2-18.2), with an average delay in diagnosis of 12 months. Follow-up was 0.3-7.9 years (average 2.1), with 104 individual bony lesions identified, with a median of 3 (range 1-9) per patient. Six patients had unifocal disease. The sites involved included the tibia (n = 19), femur (n = 14), clavicle (n = 12), vertebrae (n = 10) and fibula (n = 8). Approximately half of patients had an inflammatory arthritis at diagnosis, and two-thirds in total eventually developed an arthritis. Pustulosis occurred in eight patients (24%), severe acne in four (12%) and psoriasis in three (9%). NSAIDs were used in 91%, CSs in 82% and MTX in 38%. Two patients were treated with anti-TNF agents. Episodic disease was most common (79%), while 21% had a monophasic pattern. Clinical remission occurred in 94% of children, with prolonged remission in 17%. Seven patients did not require medications for >12 months. Conclusion CRMO is more common than previously recognized, but diagnosis may be delayed. Episodic multifocal disease was most common, but some had unifocal and/or monophasic disease. Most patients responded to NSAIDs and/or intermittent CSs, but many required DMARDs.

ObjectiveTo investigate a cohort of children with symptomatic joint hypermobility.MethodsCase notes for 318 children with joint hypermobility attending a rheumatology clinic were reviewed for clinical presentation, medical history, psychosocial factors and physical examination findings. Seven key variables were extracted and used as indicator variables in a latent class analysis to estimate the presence and number of subgroups of children with symptomatic joint hypermobility.ResultsTwo subgroups with differing clinical presentations were identified accounting for age and gender: an ‘athletic-persistent’ class (62%) characterised by higher probabilities for recurrent and chronic musculoskeletal pain, and less severe hypermobility; and a ‘systemic-profound’ class (38%) characterised by generalised hypermobility, recurrent musculoskeletal pain, gastro-oesophageal reflux and motor delay.ConclusionFindings suggest the presence of two distinct presentations of children with hypermobility. This finding may be important for clinical decision-making and management of this group of children.

This standards document outlines accepted standards of management for children, adolescents and young adults with juvenile idiopathic arthritis (JIA) in Australia. This document acknowledges that the chronic inflammatory arthritis conditions (JIA) in childhood are different diseases from inflammatory arthritis in adults and that specific expertise is required in the care of children with arthritis.

Aim Primary chilblains are an idiopathic cold-induced vasculopathy affecting the soft tissues of the hands and feet. Secondary chilblains occur in different forms of vasculitis and chronic autoimmune connective tissue disorders. Idiopathic chilblains are rarely reported in children and may generate significant anxiety to doctors and patients. We describe a cluster of idiopathic chilblains encountered over the winter of 2010 in Perth, Western Australia. Methods This is a retrospective review of patients identified from a prospectively compiled database of all new cases seen in our department. Data on history, examination, investigations, prescribed treatments and outcomes were collected. Results Thirty-two patients with isolated idiopathic chilblains were included, including 20 females and 12 males with a median age at onset of 13.5 years. Lesions were papular with signs of peripheral vasoconstriction causing acrocyanosis, and uncomfortable due to pain and/or pruritis in most. Thickening of the small joints was common where lesions involved these areas. Ulceration of lesions also occurred in some. One patient required hospitalisation for secondary bacterial infection. Most received some form of treatment including non-steroidal anti-inflammatory drugs, prednisolone or nifedipine. Most patients improved spontaneously with warmer weather or responded to cold protection advice. All had resolved completely by late spring (November). Conclusion Our cluster of chilblains was associated with an unusually cold winter in Perth 2010. It is the largest series reported in the literature, suggesting that chilblains may be more common than previously thought. Chilblains are almost always benign in nature and patients are systemically well and usually need no further investigation and only symptomatic treatment. Prompt recognition can avoid excessive investigation and anxiety, allowing appropriate simple advice and treatment.

The standardization of the criteria to evaluate improvement in rheumatic diseases has been a goal of numerous research groups. This work led to establishment of definition of response in rheumatoid arthritis (1), juvenile arthritis (2–4), systemic lupus erythematosus (SLE) both in adults (5–7) and children (8–10). The International Myositis Outcome Assessment and Clinical Studies (IMACS) group proposed a core set of outcome variables for inclusion in clinical trials in adult and juvenile inflammatory myopathies and defined the degree of change in each core set variables that is clinically meaningful, as well as guidelines for performing clinical trials (11–14). However, until now these proposals have not yet been formally validated in the context of external prospective pediatric studies or clinical trials. Although children/adolescents and adults with DM share many signs and symptoms of disease, they differ in the clinical features and outcome (15–17), and treatment approaches should consider the peculiarities of juvenile patients as well as their longer life expectancy. Therefore, all outcome measures developed for adults need to be subjected to a critical evidence-based evaluation of their measurement properties in children and adolescents. To help standardize the conduct and reporting of juvenile dermatomyositis (JDM) clinical trials and enhance identification of new therapeutic agents, the Pediatric Rheumatology International Trials Organization (PRINTO) (18), in collaboration with the Pediatric Rheumatology Collaborative Study Group (PRCSG) and with the support of the European Union and the U.S. National Institutes of Health, undertook in year 2000 a multinational effort to develop, and promulgate a core set of outcome variables and a definition of clinical improvement to evaluate response to therapy in patients with JDM and in juvenile SLE. The first two phases of the project, previously published (8;19), led to the development of a prospectively evidence-based validated core set of six variables for the evaluation of response to therapy that is now known as the provisional PRINTO/American College of Rheumatology/European League Against Rheumatism Disease Activity Core Set for the evaluation of response to therapy in JDM (PRINTO/ACR/EULAR JDM core set) (Table 1). Table 1 Final domains and suggested variables included in the final PRINTO/ACR EULAR core set for the evaluation of response to therapy in JDM (adapted from ref. (19)). In this paper we report the results of the third phase of the project, which was aimed at developing a provisional validated definition of improvement to aid in the classification of individual patients in future therapeutic trials and in current clinical practice as either improved or not improved.

Objectives. Some juvenile dermatomyositis (JDM) patients have a disease course which is refractory to multiple drug treatments. Prolonged disease activity is associated with increased mortality and morbidity. TNF-� has been identified in high levels in JDM patients who have a long disease course and calcinosis. We assessed the response of five refractory JDM patients to the anti-TNF-� monoclonal antibody, infliximab. Methods. For all five patients intravenous infliximab was initially given at a dose of 3mg/kg. Further doses were then given at weeks 2, 6 and every 8 weeks thereafter. The dose and frequency were tailored in accordance with clinical response. Clinical and laboratory data were collected prospectively. Results. We report results between 8 and 30 months after starting infliximab. Improvements were seen in all five patients as shown by positive changes in physician visual analogue scale (VAS), Childhood Myositis Assessment Score (CMAS), Childhood Health Assessment Questionnaire (CHAQ), joint range of movement and, in some, regression of calcinosis and skin signs. There were no major side effects observed with addition of infliximab to the therapeutic regime. Conclusions. Major clinical benefit was demonstrated after the initiation of infliximab in all five cases of refractory JDM.

To examine the change in health-related quality of life (HRQOL) and its determinants in children with juvenile idiopathic arthritis (JIA) treated with methotrexate (MTX).Patients were extracted from the PRINTO clinical trial which aimed to evaluate the efficacy and safety profile of MTX administered in standard, intermediate or higher doses (10, 15 and 30 mg/m(2)/week respectively). Children with polyarticular-course JIA, who were less than 18 years and had a complete HRQOL assessment were included.A total of 521 children were included. At baseline, patients with JIA showed poorer HRQOL (p0.01) than healthy children. In 207/412 (50%) and 63 (15%) children, HRQOL values were 2 standard deviations below the mean of healthy controls in the physical and psychosocial summary scale, respectively. After 6 months of treatment with standard dose MTX, there was a statistically significant improvement in all HRQOL health concepts, particularly the physical ones. Similar improvements were observed in those who did not respond to a standard dose of MTX and were subsequently randomised to a higher dose. The presence of marked disability at baseline was associated with a fivefold increased risk of retaining poor physical health after 6 months of active treatment with standard dose MTX. Other less important determinants of retaining poor physical well-being were the baseline level of systemic inflammation, pain intensity and an antinuclear-antibody-negative status.MTX treatment produces a significant improvement across a wide range of HRQOL components, particularly in the physical domains, in patients with JIA.

Juvenile idiopathic arthritis (JIA) comprises a group of heterogeneous disorders of chronic arthritis in childhood and remains the commonest pediatric rheumatic disease associated with significant long-term morbidity. Advances in understanding of the pathogenesis, better definition of disease control/remission measures, and the arrival of biological agents have improved the outcomes remarkably. Methotrexate (Mtx) remains the first-line disease modifying (DMARD) therapy for most children with JIA due to its proven efficacy and safety. Sulphosalazine (SSz) (especially for enthesitis) and leflunomide may also have a secondary role. Tumor necrosis factor inhibitors (TNF-I), alone or in combination with Mtx have shown tremendous benefit in children with polyarticular JIA, enthesitis related arthritis (ERA) and psoriatic arthritis. Tocilizumab appears very efficacious in systemic arthritis and abatacept and tocilizumab also appear to benefit polyarticular JIA; the role of rituximab remains unclear, though clearly beneficial in adult RA. TNF-I with Mtx is also effective in uveitis associated with JIA. Biologicals have demonstrated an impressive safety record in children with JIA, although close monitoring for rare but potentially dangerous adverse events, such as tuberculosis and other infections; paradoxical development of additional autoimmune diseases; and possibly an increased risk of cancers is warranted.

Aicardi-Goutieres syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutieres syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials. (c) 2015 Wiley Periodicals, Inc

It is well recognized that many if not most children and adolescents attending paediatric rheumatology clinics will have a non-inflammatory origin for their complaints or disorder. Mechanical causes are frequently identified, and hypermobility or ligamentous laxity of joints is increasingly recognized as an aetiological factor in the presentation. Such conditions include 'growing pains', recurrent lower-limb arthralgia, anterior knee pain syndromes, and back pain. Studies of significant cohorts of such patients have now been published supporting the link of ligamentous laxity to particular symptom complexes. However, much disagreement remains as to the validity of hypermobility as an aetiogical factor. What seems clear is that not all hypermobile individuals will be symptomatic or indeed possibly have any risk for specific musculoskeletal disorders in later life. Screening tools such as the Beighton score are likely to be inadequate in many paediatric populations. Along with increasing recognition of these disorders in childhood and adolescence has been the development of a multidisciplinary management approach, which usually involves predominantly allied health professionals such as podiatrists, physiotherapists and occupational therapists. The challenge remains to interpret symptoms correctly as being related to the hypermobility and to predict why such children become symptomatic. The answer is likely to involve physiological and psychosocial factors. In addition, early identification and modification of risk factors may have major implications for subsequent prevalence of many adult medical disorders such as low back pain, chronic pain syndromes and degenerative osteoarthritis.

Reflex sympathetic dystrophy (RSD) is a complex regional pain syndrome characterized by variable dysfunctions of the musculoskeletal, skin, and vascular systems. The most common features are severe persistent spontaneous pain in a limb, sensory and vascular alterations, and major associated disability, which often causes profound psychological dysfunction (1,2). RSD is characterized by spontaneous pain, swelling, dysaethesia, and allodynia usually of a distal site of the affected extremity (3,4). Other features relate to the autonomic nervous system and include cyanosis, mottling, sweating (which is less common in children), and reduction in temperature. In some cases, particularly if there is delay in recognition or treatment, more permanent or serious features may develop; these include muscle atrophy, demineralization of bone, and contractures of soft tissue around the affected joint. In the early stages of RSD, there are no specific laboratory tests available to help diagnose the condition, and the radiologic and bone scanning findings characteristic in adults are often not seen in children (5–9). The lack of diagnostic investigations, the relative lack of recognition of the condition, and the more variable clinical presentation present in children often result in a delay in diagnosis and treatment. This often is complicated by the diversity of medical opinions sought from the onset of symptoms. This may lead to a more severe and chronic presentation. Although a number of studies have reported RSD in childhood, a variety of approaches to its management have been suggested with variable or undetermined outcomes (10). RSDmay also occur in, or be associated with, a variety of other clinical conditions and may affect different areas of the body to a greater or lesser extent. There are also a variety of descriptive names that are used as synonyms for RSD, including algodystrophy, reflex neurovascular dystrophy, causalgia, Sudeck’s atrophy (although this refers to patients with the classic macular osteopenia, not often seen in children), and complex regional pain syndrome type 1 (2). In this article we prefer the older but perhaps still more commonly used term, RSD (11–13). Population studies in schoolchildren indicate that chronic or recurrent musculoskeletal pain is quite common, with back pain being the most frequent (20%), followed by limb pain (16%) and fibromyalgia (6%) (14–17). There is little work on the incidence of RSD, but 5–8% of new referrals to North American pediatric rheumatology centers have a diagnosis of idiopathic musculoskeletal pain syndromes, a small percentage of which are RSD (18,19). Idiopathic musculoskeletal pain syndromes have been described in patients as young as 3 years of age, though RSD has not been reported at this age. The majority of reports involve children in late childhood or early adolescence, with a mean age of onset of 12–13 years and a higher frequency in girls than boys ( 4:1) (3,4,13,20–22). There have been no reports of specific ethnic differences in the presentation of RSD. Currently, there is no single or specific biologic cause identified or pathogenetic pathway described for RSD, and it is clear that the clinical features may vary widely from children to adults. The etiology is likely to be multifactoral in some children. In many pediatric cases, however, there is no or only a very minor precipitating incident; psychological factors may have greater influence. This hypothesis is supported with the differences found between technetium bone scintigraphy in children compared with adults and by the fact that children respond more readily to physical therapies (4,23). However, it appears that the triggering factor in many children is related to injury, illness, or psychological distress in any combination (3–5,8,9,13–17,20,24–39), in contrast to adults in whom surgery or myocardial infarction often precedes the onset of RSD (31,32,40). Susan M. Maillard, MSc, SRP, MCSP, Karen Davies, MB, BS, MRCP, Patricia M. Woo, MB, BS, PhD, FRACP, Kevin J. MurrayMB, BS, FRACP (current address: Princess Margaret Hospital for Children, Perth, Western Australia): Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom; Raju Khubchandani, MD, FRACP: Jaslock Hospital and Research Centre, Mumbai, India. Address correspondence to Susan M. Maillard, MSc, SRP, MCSP, Juvenile Dermatomyositis Research Centre, Rheumatology Unit, Ground Floor, Philip Ullmann Wing, 30 Guilford Street, London, WC1N 1EH, United Kingdom. Email: S.Maillard@ich.ucl.ac.uk. Submitted for publication March 31, 2003; accepted in revised form September 15, 2003. Arthritis & Rheumatism (Arthritis Care & Research) Vol. 51, No. 2, April 15, 2004, pp 284–290 DOI 10.1002/art.20249 © 2004, American College of Rheumatology

To identify preliminary core sets of outcome variables for disease activity and damage assessment in juvenile systemic lupus erythematosus (JSLE) and juvenile dermatomyositis (JDM).Two questionnaire surveys were mailed to 267 physicians from 46 different countries asking each member to select and rank the response variables used when assessing clinical response in patients with JSLE or JDM. Next, 40 paediatric rheumatologists from 34 countries met and, using the nominal group technique, selected the domains to be included in the disease activity and damage core sets for JSLE and JDM.A total of 41 response variables for JSLE and 37 response variables for JDM were selected and ranked through the questionnaire surveys. In the consensus conference, domains selected for both JSLE and JDM activity or damage core sets included the physician and parent/patient subjective assessments and a global score tool. Domains specific for JSLE activity were the immunological tests and the kidney function parameters. Concerning JDM, functional ability and muscle strength assessments were indicated for both activity and damage core sets, whereas serum muscle enzymes were included only in the activity core set. A specific paediatric domain called 'growth and development' was introduced in the disease damage core set for both diseases and the evaluation of health-related quality of life was advised in order to capture the influence of the disease on the patient lifestyle.We developed preliminary core sets of measures for disease activity and damage assessment in JSLE and JDM. The prospective validation of the core sets is in progress.

The last few decades have produced major advances in the understanding of clinical aspects of inflammatory myositis disorders, both in children and adults. Though relatively rare in childhood, these conditions are often quite severe and require intensive treatments for considerable periods of time. Significant morbidity and occasional mortality still occur despite improvements in outcome. This improved outcome has resulted in part from the novel or better applications of medications already in use, as well as the availability of newer drugs. Few of these have been designed specifically for use in inflammatory myositis but have been drawn from therapeutic trials in other rheumatic disorders and areas of medicine such as oncology and transplantation medicine. Just as important have been the international efforts to design and validate specific outcome measures for all aspects of these disorders, both in childhood and adults, particularly to support the conduct of therapeutic trials. It is highly likely that as improvements in understanding of pathogenesis occur, more specific treatments with drugs such as biological agents will replace the more traditional therapeutic approaches and perhaps designed specifically on a patient-by-patient basis. This review highlights the important advances of the last decade and describes a management approach shared by many of the workers in this field. It focuses primarily on juvenile onset dermatomyositis (JDM) as this is the most common disorder seen, and experience with JDM forms the basis of management of the other disorders.

The management of juvenile idiopathic arthritis (JIA) has undergone dramatic changes in the last decade with undoubtedly great benefit for many patients. In particular, more effective use of available drugs and the application of newly discovered drugs have been responsible for much of this improvement. Methotrexate is the gold standard for management of moderate to severe polyarthritis. Other disease-modifying antirheumatic drugs (DMARDs) such as sulphasalazine and cyclosporine are finding a specific role for resistant disease where they may be used in combination with methotrexate, for example. The introduction of anti-TNF agents, such as etanercept, is likely to herald a major shift to the use of biological agents in those intolerant to, or unresponsive to, standard DMARD therapy. DMARDs provide major steroid spring effect in many children with severe JIA with the hope that osteoporosis and growth failure will be reduced. More judicious use of corticosteroids and techniques such as intravenous 'pulse therapy' rather than long-term high-dose use of oral corticosteroids are also major changes. Intra-articular corticosteroids are commonly used in children with oligoarticular JIA and as a useful adjunct to DMARD therapy in children with other forms of JIA. Autologous stem cell transplantation is an exciting new development currently restricted to use in patients with very severe, resistant disease. Modifications of technique, experience and increased safety may make this a more widely applicable technique, in particular for patients with a poor prognosis, such as those with systemic JIA. Although the focus of this chapter is on drug therapy, multidisciplinary team management for children with chronic arthritis focusing on the physical, nutritional, intellectual and psychosocial wellbeing of the child will continue to be important.

Objectives The objectives of this paper are to prospectively determine the incidence of paediatric systemic lupus erythematosus (pSLE) in Australia as well as describe the demographics, clinical presentation and one-year outcome. Study design Newly diagnosed cases of pSLE were ascertained prospectively from October 2009 to October 2011 through the Australian Paediatric Surveillance Unit (a national monthly surveillance scheme for notification of childhood rare diseases) as well as national subspecialty groups. Questionnaires were sent to notifying physicians at presentation and at one year. Results The annual incidence rate was 0.32 per 105 children aged less than 16 years. The incidence was significantly higher in children of Asian or Australian Aboriginal and Torres Strait Islander parents. Approximately one-third of children underwent a renal biopsy at presentation and 7% required dialysis initially although only one child had end-stage kidney disease (ESKD) at one-year follow-up. Conclusion The incidence of pSLE in Australia is comparable to that worldwide with a significantly higher incidence seen in children of Asian and Australian Aboriginal and Torres Strait Islander backgrounds. Renal involvement is common but progression to ESKD, at least in the short term, is rare.

Objective To define the onset and duration of effect of the HLA alleles that are associated with disease susceptibility and protection in juvenile rheumatoid arthritis (JRA) and 2 of its subtypes. Methods We typed 680 patients with JRA and 254 ethnically matched unrelated controls for HLA class I and II genes. The frequency of each allele was calculated for each of the age-at-onset, onset type, and sex categories and plotted against the allele frequency in the control population. Survival analysis (with onset of disease as the terminating event) was used to calculate the age by which 50% (St0.5) and 80% (St0.2) of the children with particular alleles and combinations of alleles develop disease. This allele-specific survival analysis also allowed for the comparison of the overall survival functions for the various JRA subtype and sex categories. Results Certain alleles are strongly associated with early susceptibility to pauciarticular JRA, including HLA–A2, DR8, DR5, and DPB1*0201. Fifty percent of the children carrying at least 1 of these alleles had disease onset prior to their third birthday. Among children who carried HLA–A2 and any 2 HLA–DR alleles (DR3, DR5, DR6, or DR8), the median age at the onset of pauciarticular disease was 2.7 years. Combinations of A2 and DPB1*0201 and one DR allele narrowed the window further to a median age at onset of 2.4 years. B27 and DR4 were associated with protection early in life but with increased risk later in childhood, with St0.5 values of 7.3 and 6.6 years, respectively, for pauciarticular JRA and St0.5 values of 10.2 and 10.7 years, respectively, for polyarticular JRA. Sex strongly influenced the age at which many of the alleles have their effect. Conclusion These data define at what age and for how long various HLA alleles influence susceptibility and protection (window-of-effect) in patients with JRA. In addition, these data establish more clearly the boundaries of ages-at-onset for 2 of the subtypes of the disease.

Objective To identify features of the T cell receptors (TCRs) present on clonally expanded T cells in the joints of patients with similar types of childhood rheumatic disease. Vbeta8 and Vbeta20 TCRs were selected as prototypic for polyarticular juvenile rheumatoid arthritis (JRA) and pauciarticular/juvenile spondylarthropathy (SpA), respectively. Methods The portion of the TCR beta chain involved in antigen recognition in the synovial tissue, synovial fluid, and peripheral blood from patients with JRA and juvenile SpA was cloned and sequenced. The frequency of expanded clonotypes, size of expansions, the Jbeta region, and sequence motifs were determined for >2,000 sequences. Results The majority of Vbeta20 and Vbeta8 clonal expansions were found in the joint rather than the peripheral blood. While instances of both Vbeta8 and Vbeta20 clonal expansion were detected in all disease types, the features of these expanded clonotypes were specific for disease type and Vbeta family. For example, Vbeta20 clonal expansion was characterized by many small expanded clonotypes in samples from patients with pauciarticular JRA and juvenile SpA while single large Vbeta8-specific expansions were found only in patients with polyarticular disease. Motifs specific to individual patients were identified, and for Vbeta20 clonotypes, a motif was found in synovial tissue samples. Conclusion Identification of common TCR features in oligoclonal expansions within individual patients and between patients with the same type of JRA suggests the recognition of a common or limited group of antigens in these diseases.

Objective To compare the safety and efficacy of parenteral methotrexate (MTX) at an intermediate dosage (15 mg/m2/week) versus a higher dosage (30 mg/m2/week) in patients with polyarticular-course juvenile idiopathic arthritis (JIA) who failed to improve while receiving standard dosages of MTX (8–12.5 mg/m2/week). Methods In the screening phase, 595 patients who were newly started on a standard dose of MTX were followed up for 6 months. Subsequently, the nonresponders, defined according to the American College of Rheumatology (ACR) pediatric 30% improvement criteria (pediatric 30), were randomized to receive an intermediate dose or higher dose of parenteral MTX for an additional 6 months. Improvement in the screening and randomization phase was defined by the ACR pediatric 30 response, as well as by the 50% and 70% response levels (ACR pediatric 50 and ACR pediatric 70, respectively). Results In the screening phase, after receiving standard doses of MTX, 430 patients (72%) improved according to the ACR pediatric 30, while 360 (61%) met the ACR pediatric 50 and 225 (38%) met the ACR pediatric 70; among these patients, 69 (12%) also met the definition of complete disease control. Of the 133 nonresponders, 80 were randomized to receive an intermediate dose or higher dose of MTX. In the randomization phase, the ACR pediatric 30 response rate was 25 of 40 children (62.5%) in the intermediate-dose group versus 23 of 40 children (57.5%) in the higher-dose group. An ACR pediatric 50 response rate was attained by 23 patients (57.5%) receiving an intermediate dose versus 22 (55%) in the higher-dose group. An ACR pediatric 70 response rate was seen in 18 children (45%) receiving an intermediate dose versus 19 (47.5%) receiving a higher dose. Five children (12.5%) in the intermediate-dose group versus 4 (10%) receiving the higher dose of MTX also met the definition of complete disease control. None of the intergroup differences in response rate were significant. There were no significant differences in the frequency of adverse events or laboratory abnormalities between the 2 randomized groups. Conclusion This study shows that the plateau of efficacy of MTX in JIA is reached with parenteral administration of 15 mg/m2/week and that a further increase in dosage is not associated with any additional therapeutic benefit. MTX should be administered for up to 9–12 months to appreciate its full therapeutic effect.

Juvenile chronic arthritis (JCA) is a heterogeneous group of chronic arthropathies affecting approximately 1–3 children per 1000. The initial oversimplified classification into pauciarticular, polyarticular, and systemic onset types has been expanded in a World Health Organisation-International League Against Rheumatism report to include seven different types of disease.1 It is clear that the majority of children with JCA have a different disease from adults with rheumatoid arthritis, although the chronic arthropathies have some common clinical and pathological features. As a group, these diseases are generally considered to be autoimmune in origin with the evidence supporting this varying between types. There is a general female preponderance, characteristic chronic inflammatory infiltrates in the synovium and immune responses characterised by autoantibodies including antinuclear antibodies (ANA), IgM rheumatoid factor, and antibodies to heat shock proteins and the oncoprotein DEK. In addition and in common with many other autoimmune diseases, there are extensive and well documented associations with genetic markers, primarily, but not exclusively, within the major histocompatibility complex (MHC) or HLA region on the short arm of chromosome 6. It is anticipated that environmental triggering agents are also involved in the pathogenic process. In a recent review of a related disease, rheumatoid arthritis, the contribution of HLA genetics to pathogenesis was estimated to be approximately 37% with as yet unknown genes contributing further, with the balance being deemed largely due to environmental factors.2 The purpose of this review is to consider the relative contributions of genetic versus environmental factors as being causal in the various types of JCA. JCA is rarely familial so that a low index of suspicion for a simple genetic basis is in order. In early studies reported, Dr Barbara Ansell and Professor Eric Bywaters were able to identify family disease and concordance in twins. Subsequently multiplex families and sibling …

In adults with inflammatory arthritis, insulin resistance (IR) is associated with diabetes and cardiovascular disease. Interleukin-6 (IL-6) is postulated to play a mechanistic role in IR.

BACKGROUND. Efforts to improve local control and survival by increasing the dose of once-daily radiation therapy beyond 70 Gray (Gy) for patients with malignant gliomas have as yet been unsuccessful. Hyperfractionated radiation therapy (HF) should allow for delivery of a higher total dose without increasing normal tissue late effects, whereas accelerated hyperfractionated radiation therapy (AHF) may minimize tumor repopulation by shortening overall treatment time. The Radiation Therapy Oncology Group (RTOG) conducted a randomized Phase I/II study of escalating doses of HF and AHF with carmustine (bis-chloroethyl nitrosourea [BCNU]) for adults with supratentorial glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA). Primary study endpoints were overall survival and acute and chronic treatment-related toxicity. METHODS. From 1983 to 1989, 786 patients with supratentorial gliomas (81% with GBM and 19% with AA) were stratified by histology, age, and performance status and randomized to receive partial brain irradiation, utilizing either HF (1.2 Gy twice daily to doses of 64.8, 72, 76.8, or 81.6 Gy) or AHF (1.6 Gy twice daily to doses of 48 or 54.4 Gy). All patients received carmustine. The distribution of prognostic factors was similar in all arms. RESULTS. There were 747 eligible and analyzable patients among 786 enrolled patients (95%). Two patients had a Grade 5 and 65 patients had a Grade 4 chemotherapy toxicity. Two patients in the 81.6 Gy arm experienced late Grade 4 radiation toxicity and there was 1 late radiation-associated death in the 54.4 Gy arm. The rate of Grade 3 or worse radiation toxicity at 5 years, calculated by the delivered dose level, was 3% in the lowest total dose arms (48 and 54.4 Gy), 4% in the intermediate dose arms (64.8 and 72 Gy), and 5% in the highest dose arms (76.8 and 81.6 Gy) (P = 0.54). Survival rates at 2 and 5 years were: 21% and 11%, respectively, for all patients; 62% and 41%, respectively, for AA patients; and 10% and 4%, respectively, for GBM patients. There were no significant differences between the treatment arms with regard to median survival time (MST), when analyzed by the originally assigned dose. The MST for all patients varied between 10.8 months and 12.7 months (P = 0.59); between 9.6 months and 11 months for patients with GBM (P = 0.43); and between 30.4 months and 85.8 months for patients with AA (P = 0.78). Analysis of the survival rates for all patients by dose received rather than by dose assigned revealed a 14% 5-year survival rate for the lower HF doses (64.8 and 72 Gy), 11% for the higher doses (76.8 and 81.6 Gy), and 10% for the AHF doses (48 and 54.4 Gy)(P = 0.1). The subgroup of AA patients had a better MST (49.9 months) in the lower received HF doses than in the higher HF doses (34.6 months)(P = 0.35). In contrast, GBM patients who received the higher HF doses had survival superior to the patients in the AHF arms (MST of 11.6 months and 10.2 months, respectively; P = 0.04). CONCLUSIONS. The use of HF with BCNU and dose escalation up to 81.6 Gy is both feasible and tolerable, although late toxicity increases slightly with increasing dose. The best MST with the least toxicity were observed for AA in the lower received HF doses (72 and 64.8 Gy). Accordingly, 72 Gy in two 1.2 Gy fractions was used as the investigational arm of a completed Phase III trial (RTOG 90-06).

JRA is a complex of disease subtypes which are normally identified by clinical features such as age of onset and extent of joint involvement both at onset and during the course of the disease. We previously identified an association between TCR BV6S1 null allele and one subgroup of early-onset pauciarticular patients positive for HLA-DQA1∗0101, an HLA haplotype predisposing to a polyarticular course of the disease. In this report we extend this observation by identifying an increased prevalence of this nonfunctional or null allele in the patients with a polyarticular disease course regardless of the mode of onset. This increase was most prominent in clinical subsets that have early onset of the disease and a polyarticular outcome. In one clinical group, stratification of patients by the HLA allele DQA1∗0101 strengthened the association considerably. This implies that there is an increased genetic load defined by specific alleles of both MHC and TCR genes.

The measurement of function in children with rheumatic diseases is an intimate part of not only the initial diagnostic work-up, but also of every clinic visit during the course of these chronic diseases. This article focuses on the development of specific and general instruments used to systematically measure function and thus, outcome of the rheumatic diseases and their treatments. Reference is made to instruments developed for use in the general pediatric and adult rheumatology population as a basis for the discussion of the instruments in use in pediatric rheumatology. Specifically, the dimensions of physical function, psychosocial impact, economic impact and quality of life are addressed.

Background. Confounding biologic factors, including histologic grade, may influence the outcome of adult patients with malignant gliomas more than may modifications in therapeutic approach. Any clinical trial design for malignant gliomas in adults must account for such biologic factors, including the accurate identification of the two histologic subgroups astrocytoma with anaplastic foci (AAF) or glioblastoma multiforme (GBM), which are associated with distinctly different survival outcomes. This paper examines the need for a central pathology review before entry of patients in cooperative group clinical trials stratified by histologic grade. Methods. Pathology slides from Radiation Therapy Oncology Group (RTOG) trial 83-02, a randomized Phase II study of hyperfractionated and accelerated hyperfractionated radiation therapy and carmustine for malignant gliomas, provided 747 analyzable cases, with 680 (91%) available for central pathology review. This review was performed by a single pathologist according to RTOG/Eastern Cooperative Oncology Group histopathologic criteria. The kappa statistic was used to measure agreement between the institutional and central classification of AAF and GBM. The influence of misclassification was examined using computer simulation of varying clinical trial sizes (n = 25, 50, or 200). The effect on the statistical power of trials (n = 200) with varying mixtures of AAF and GBM tumors was investigated using computer simulations. Results. Of 159 tumors classified as AAF by institutional pathology review, only 66% (105) were classified as AAF (AAF/AAF) by central review, and 54 of these cases (34%) were classified as GBM (GBM/AAF), whereas 96% (501) of 521 institutionally classified as GBM (GBM/GBM) were similarly classified by central review. Computer simulations demonstrated a 59% underestimation in the median survival (1.82 vs. 4.49 years) for trials of patients with institutionally defined AAF compared to patients with centrally defined AAF in studies of 200 patients, resulting from the addition of poor prognosis of GBM in the trial. Misclassification can also substantially reduce the statistical power of a clinical trial. In one of the simulation studies, statistical power was reduced from 65% to 14% if 50% of the patients were to receive an inaccurate histologic classification. Even greater losses in power are possible in many plausible clinical settings. Conclusions. This examination of a central versus an institutional pathology review demonstrates a low level of agreement on AAF classification and a high level of concordance on GBM classification. The results indicate the need to adjust sample size for trials of both AAF and GBM tumors to have adequate statistical power. A central pathology review remains essential for trial entry for patients with AAF and could be omitted for trials enrolling patients with GBM only

Primary chilblains are an idiopathic cold-induced vasculopathy affecting the soft tissues of the hands and feet. Secondary chilblains occur in different forms of vasculitis and chronic autoimmune connective tissue disorders. Idiopathic chilblains are rarely reported in children and may generate significant anxiety to doctors and patients. We describe a cluster of idiopathic chilblains encountered over the winter of 2010 in Perth, Western Australia.This is a retrospective review of patients identified from a prospectively compiled database of all new cases seen in our department. Data on history, examination, investigations, prescribed treatments and outcomes were collected.Thirty-two patients with isolated idiopathic chilblains were included, including 20 females and 12 males with a median age at onset of 13.5 years. Lesions were papular with signs of peripheral vasoconstriction causing acrocyanosis, and uncomfortable due to pain and/or pruritis in most. Thickening of the small joints was common where lesions involved these areas. Ulceration of lesions also occurred in some. One patient required hospitalisation for secondary bacterial infection. Most received some form of treatment including non-steroidal anti-inflammatory drugs, prednisolone or nifedipine. Most patients improved spontaneously with warmer weather or responded to cold protection advice. All had resolved completely by late spring (November).Our cluster of chilblains was associated with an unusually cold winter in Perth 2010. It is the largest series reported in the literature, suggesting that chilblains may be more common than previously thought. Chilblains are almost always benign in nature and patients are systemically well and usually need no further investigation and only symptomatic treatment. Prompt recognition can avoid excessive investigation and anxiety, allowing appropriate simple advice and treatment.

Background/Purpose: In adults with inflammatory arthritis, insulin resistance (IR) is associated with diabetes and cardiovascular disease. Interleukin-6 (IL-6) is postulated to play a mechanistic role in IR. The aim of this study was to evaluate the degree of IR among children with systemic juvenile idiopathic arthritis (sJIA) and to determine whether treatment with tocilizumab (TCZ) results in attenuation of IR in sJIA. Methods: Patients from TENDER[1] were included if baseline and week 6 fasting insulin were measured. Glucocorticoid tapering was not permitted until week 6. Insulin sensitivity was quantified using the homeostatic model of insulin resistance (HOMA-IR). Patients were classified as having IR if their HOMA-IR was ≥2.2 U. Change in HOMA-IR after 6 weeks was assessed using paired t-test. Baseline associations with HOMA-IR and factors predicting change of HOMA-IR from baseline were assessed using regression analyses. Factors changing in association with HOMA-IR change were assessed. Results: Ninety-two patients with sJIA were analyzed. 62 were randomly assigned to TCZ and 30 to placebo, 12 of whom required escape therapy with TCZ by week 6. At baseline, 40 patients (43%) had IR. Baseline HOMA-IR was associated with higher standardized body mass index and higher IL-6 levels (β-coefficients [95% CI]: 0.20 [0.05, 0.35] and 0.019 [0.001, 0.038], respectively) but not with JADAS, CRP, active joint count, or presence of fever. Of the 74 patients who received TCZ, 34 (46%) had IR at baseline, including 4 patients who escaped from the placebo arm, compared with 6/18 (33%) who received only placebo. IR patients treated with TCZ but not placebo had significant reductions in HOMA-IR at week 6 (1). Across all IR patients, improvement in JADAS and active joint count was not associated with improvement in HOMA-IR (β-coefficients [95% CI]: 0.04 [−0.07, 0.14] and 0.08 [−0.06, 0.22], respectively). Table 1. Change in HOMA-IR After 6 Weeks of TCZ Treatment in Children With sJIA in the TENDER Study Change in HOMA-IR Mean (95% CI) pa a NS, not significant; PBO, placebo. aPaired t-test. TCZ (n = 34) −0.2 (−3.8, −0.2) 0.03 PBO (n = 6) 0 (−1.7, 1.6) NS Conclusion: After only 6 weeks of TCZ treatment, HOMA-IR was improved in IR patients with sJIA in the presence of unchanged glucocorticoid dose. These data support a mechanistic contribution of IL-6 to IR in vivo in humans.

Osteonecrosis is a well-recognised complication of current childhood acute lymphoblastic leukaemia (ALL) therapy. There are few studies on the medical management of osteonecrosis in this setting. We studied the therapeutic and radiological effects of oral and intravenous bisphosphonate use compared with standard care as treatment for osteonecrosis in this population.Patients who developed osteonecrosis as a complication of ALL therapy between 1994 and 2007 were treated at a single paediatric institution. Of 17 patients, 9 were commenced on bisphosphonates and 8 treated conservatively. Both groups were observed with time. Pain, analgesic requirement and musculoskeletal function were assessed monthly. Affected joints were radiologically imaged at set intervals. Each scan was graded using an ellipsoid method to give the total volume of osteonecrosis, by blinded radiologic examination.Three of six patients treated with oral alendronate showed clinical improvement. The three patients that had no improvement were subsequently treated with intravenous pamidronate. All six patients treated with intravenous pamidronate showed clinical improvement. Seven of eight conservatively treated patients deteriorated clinically. All patients demonstrated reduction in the radiological burden of osteonecrosis with time. There was no difference in the rate of reduction between conservative and bisphosphonate arms.Bisphosphonate use, in particular pamidronate, improved pain scores, analgesic requirement and musculoskeletal function in patients with osteonecrosis occurring as a complication of childhood ALL therapy. Objective radiologic benefit of bisphosphonate treatment could not be demonstrated. Risks, benefits and long-term outcome of bisphosphonate use in this population should be addressed in a larger prospective, randomised trial.

A 6 year old female with symptoms of small bowel obstruction underwent an exploratory laparotomy which revealed widespread evidence of inflammatory fibrotic adhesions involving the jejunal mesentery. In view of persistent growth failure, chronic anaemia, elevated acute phase reactants and imaging evidence of a diffuse progressive inflammatory process, the child was treated with corticosteroids and methotrexate with complete response. The literature on juvenile idiopathic sclerosing mesenteritis has been reviewed.

Submitted by Guilherme Lemeszenski (guilherme@nead.unesp.br) on 2014-02-26T17:28:15Z No. of bitstreams: 1 WOS000244138100006.pdf: 158213 bytes, checksum: ebf0e660bfdbefc0e3aceeba876f1006 (MD5) Made available in DSpace on 2014-02-26T17:28:15Z (GMT). No. of bitstreams: 1 WOS000244138100006.pdf: 158213 bytes, checksum: ebf0e660bfdbefc0e3aceeba876f1006 (MD5) Previous issue date: 2007-02-15 Submitted by Vitor Silverio Rodrigues (vitorsrodrigues@reitoria.unesp.br) on 2014-05-20T15:29:57Z No. of bitstreams: 1 WOS000244138100006.pdf: 158213 bytes, checksum: ebf0e660bfdbefc0e3aceeba876f1006 (MD5) Made available in DSpace on 2014-05-20T15:29:57Z (GMT). No. of bitstreams: 1 WOS000244138100006.pdf: 158213 bytes, checksum: ebf0e660bfdbefc0e3aceeba876f1006 (MD5) Previous issue date: 2007-02-15 Objective. To investigate the proxy-reported health-related quality of life (HRQOL) and its determinants in patients with juvenile idiopathic arthritis (JIA).Methods. In this multinational, multicenter, cross-sectional study, HRQOL of patients with JIA was assessed through the Child Health Questionnaire (CHQ) and was compared with that of healthy children of similar age from the same geographic area. of joint inflammation, Childhood Health Assessment Questionnaire (CHAQ), and erythrocyte sedimentation rate.Results. A total of 6,639 participants (3,324 with JIA and 3,315 healthy) were enrolled from 32 countries. The mean SD physical and psychosocial summary scores of the CHQ were significantly lower in patients with JIA than in healthy children (physical: 44.5 +/- 10.6 versus 54.6 +/- 4.0, P < 0.0001; psychosocial: 47.6 +/- 8.7 versus 51.9 +/- 7.59 P < 0.0001), with the physical well-being domain being most impaired. Patients with persistent oligoarthritis had better HRQOL compared with other subtypes, whereas HRQOL was similar across patients with systemic arthritis, polyarthritis, and extended oligoarthritis. A CHAQ score > 1 and a pain intensity rating > 3.4 cm on a 10-cm visual analog scale were the strongest determinants of poorer HRQOL in the physical and psychosocial domains, respectively.Conclusion. We found that patients with JIA have a significant impairment of their HRQOL compared with healthy peers, particularly in the physical domain. Physical well-being was mostly affected by the level of functional impairment, whereas the intensity of pain had the greatest influence on psychosocial health. Univ Genoa, Pediat Rheumatol Int Trials Org, IRCCS G Gaslini, I-16147 Genoa, Italy IRCCS G Gaslini, Serv Epidemiol & Biostat, Genoa, Italy Hop Necker Enfants Malad, Paris, France Univ Estadual Paulista, Botucatu, SP, Brazil Princess Margaret Hosp Children, Perth, WA, Australia Hanyang Univ, Med Ctr, Hosp Rheumat Dis, Seoul 133791, South Korea Univ Ziekenhuis Gent, Ctr Kinderreumatol, Ghent, Belgium Allgemeines Krankenhaus Eilbeck, Hamburg, Germany Inst Nacl Rehabil, Mexico City, DF, Mexico Wilhelmina Childrens Hosp, Utrecht, Netherlands Univ Helsinki, Cent Hosp, Hosp Children & Adolescents, Helsinki, Finland Fac Med 1, Prague, Czech Republic Gen Fac Hosp, Prague, Czech Republic Inst Madrileno Salud, Madrid, Spain Aristotle Univ Thessaloniki, Ippokration Gen Hosp, Thessaloniki, Greece Hop Univ Geneva, Geneva, Switzerland RAMS, Inst Rheumatol, Moscow, Russia Cerrahpasa Tip Fak, Istanbul, Turkey Cleveland Clin Fdn, Cleveland, OH 44195 USA HealthActCHQ, Boston, MA USA Univ Genoa, IRCCS G Gaslini, Genoa, Italy Univ Estadual Paulista, Botucatu, SP, Brazil

s. To estimate dental disease indices and temporomandibular joint (TMJ) dysfunction in children with juvenile idiopathic arthritis (JIA).Indices were recorded for dental caries, bacterial dental plaque, gingival inflammation, and TMJ dysfunction in children with JIA and matched controls.There was no significant difference in dental caries experience or the mean plaque score between children with JIA and controls. The mean gingivitis score for the permanent teeth only was significantly greater in the JIA children compared with the controls (p = 0.02). There was a significantly greater proportion of children with JIA with signs of both left and right TMJ dysfunction (p = 0.05, p = 0.02) and symptoms (p = 0.0001, p = 0.0001) compared with controls.The low caries rate was attributed to the fact that children with JIA had received preventive dental care from an early age combined with sugar free medication.

Over the previous three decades there have been a number of dramatic changes in our understanding of both the pathogenesis and epidemiology of the rheumatic diseases of childhood. Improvements in the classification of paediatric-onset arthritides and international collaboration in terms of multicentre research have led to the development of new therapeutic agents and better methods of outcome assessment for these chronic and often disabling conditions. Fortunately for children with paediatric rheumatic diseases treatment regimes are now available that provide excellent disease control for many and remission induction for some. Challenges include clearer definition of the genetics and pathogenesis of the diseases, delineation of reliable biological markers for diagnosis and monitoring of disease activity. The future should also herald early identification of those with a poorer prognosis, together with the design of more powerful, safer and cheaper remission-inducing agents, given to the right patients at the right time.

OBJECTIVE: To devise new tools to assess activity and damage in patients with idiopathic myopathies (IIM). METHODS: An international multidisciplinary consensus effort to standardize the conduct and reporting of the myositis clinical trials has been established. Two tools, known as the myositis intention to treat index (MITAX) and the myositis disease activity assessment visual analogue scale (MYOACT), have been developed to capture activity in patients with IIM. In addition, the myositis damage index (MDI) has been devised to assess the extent and severity of damage developing in different organs and systems. These measures have been reviewed by the myositis experts participating in the International Myositis Assessment and Clinical Studies (IMACS) group and have been found to have good face validity and to be comprehensive. The instruments were assessed in two real patient exercises involving patients with adult dermatomyositis and inclusion body myositis. RESULTS: The reliability of MITAX, MYOACT and MDI, measured by the intraclass correlation coefficient among the physicians, and the inter-rater reliability, as assessed by variation in the physicians' rating of patients, was fair to good for most aspects of the tools. Reliability and inter-rater agreement improved at the second exercise after the participants had completed additional training. CONCLUSIONS: The MITAX, MYOACT and MDI tools, which are now undergoing validity testing, should enhance the consistency, comprehensiveness and reliability of disease activity and damage assessment in patients with myositis.

The management of juvenile idiopathic arthritis (JIA) has undergone dramatic changes in the last decade with undoubtedly great benefit for many patients. In particular, more effective use of available drugs and the application of newly discovered drugs have been responsible for much of this improvement. Methotrexate is the gold standard for management of moderate to severe polyarthritis. Other disease-modifying antirheumatic drugs (DMARDs) such as sulphasalazine and cyclosporine are finding a specific role for resistant disease where they may be used in combination with methotrexate, for example. The introduction of anti-TNF agents, such as etanercept, is likely to herald a major shift to the use of biological agents in those intolerant to, or unresponsive to, standard DMARD therapy. DMARDs provide major steroid spring effect in many children with severe JIA with the hope that osteoporosis and growth failure will be reduced. More judicious use of corticosteroids and techniques such as intravenous 'pulse therapy' rather than long-term high-dose use of oral corticosteroids are also major changes. Intra-articular corticosteroids are commonly used in children with oligoarticular JIA and as a useful adjunct to DMARD therapy in children with other forms of JIA. Autologous stem cell transplantation is an exciting new development currently restricted to use in patients with very severe, resistant disease. Modifications of technique, experience and increased safety may make this a more widely applicable technique, in particular for patients with a poor prognosis, such as those with systemic JIA. Although the focus of this chapter is on drug therapy, multidisciplinary team management for children with chronic arthritis focusing on the physical, nutritional, intellectual and psychosocial wellbeing of the child will continue to be important.

The scleroderma disorders remain challenging conditions in pediatric rheumatology to understand pathologically and indeed for which to provide care. It is clear that much progress is being made in the clinical approach to understanding this group of group of disorders. It seems likely that the different lesions of LS may represent unique immunopathogenic mechanisms or perhaps reflect unique genetic or other characteristics of the patients themselves. To take advantage of the revolution in therapies now occurring in rheumatology it is critical that controlled clinical trials are developed with appropriate agreed upon outcome measures for both localized and systemic disease.

OBJECTIVE To assess the expression of tumor necrosis factor alpha (TNF alpha), TNF beta, and their receptors in synovia of patients with juvenile rheumatoid arthritis (JRA) and juvenile spondylarthropathy (JSpA), and to determine similarities with and differences from adult RA. METHODS Twenty-eight synovial tissue samples from patients with JRA, 6 from patients with JSpA, and 6 from patients with RA, selected for the presence of inflammatory infiltrates, were analyzed for the expression of TNF alpha, TNF beta, and their receptors (p55 and p75 TNFR), utilizing the dual approach of reverse transcriptase-polymerase chain reaction and immunohistochemistry analysis. RESULTS The presence of both TNF alpha and TNF beta expression was demonstrated in most JRA and JSpA tissues, although samples from patients with pauciarticular JRA had somewhat lesser amounts of these cytokines. TNF beta expression correlated significantly with the occurrence of lymphocytic aggregates in tissues. Staining with monoclonal antibodies specific for the p55 and p75 receptors revealed that a diverse range of cell types expressed the receptors, with the most intense p55 staining on vascular endothelial cells. In the vast majority of synovial tissues, far greater numbers of cells expressed the p55 form of the receptor than the p75 form. CONCLUSION JRA and JSpA synovia are characterized by the presence of TNF alpha, TNF beta, and cells expressing TNFR. These findings provide further evidence that TNF, through autocrine/paracrine mechanisms, may amplify local inflammation, leading to joint destruction. The prominence of TNF beta in the synovium in particular subgroups of JRA patients and in JSpA patients may be a distinguishing feature of these diseases.