Publications by authors named "Joyce E Davidson"

27 Publications

  • Page 1 of 1

Chronic non bacterial osteitis- a multicentre study.

Pediatr Rheumatol Online J 2018 Nov 22;16(1):74. Epub 2018 Nov 22.

Departments of Paediatric Rheumatology and Immunology, Bristol Royal Hospital for Children, Bristol, BS2 8BJ, UK.

Objective: To understand the demographics, clinical features and treatment outcomes of Chronic Non-bacterial Osteitis (CNO) from three tertiary paediatric rheumatology services in the United Kingdom.

Methods: Children less than 18 years of age diagnosed with CNO between 2001 to 2016 from one tertiary service and between 2001 to 2017 from two tertiary services were included. Clinical notes were reviewed and all pertinent data were collected on a pre-defined proforma. One hundred and thirty one patients were included in the study. The Bristol diagnostic criteria were applied retrospectively.

Results: Retrospective analysis of the data showed that the disease was more common in girls than boys (2.5:1), median age at onset of symptoms was 9.5 years (IQR 8 to 11 years). Bone pain was the predominant symptom in 118/129 (91.4%) followed by swelling in 50/102 (49.01%). Raised inflammatory markers were present in 39.68% of the patients. Whole body Magnetic Resonance Imaging (MRI) was a useful diagnostic tool. Metaphyses of long bones were most often involved and the distal tibial metaphyses 65/131 (49.6%) was the most common site. Non-steroidal anti-inflammatory drugs were used as first line (81.67%) followed by bisphosphonates (61.79%). Treatment was escalated to a TNF blocker when response to bisphosphonates was suboptimal. The disease was in remission in 82.4% of the patients during the last follow up.

Conclusion: Our multicentre study describes features and outcomes of CNO in a large number of patients in the United Kingdom.

Significance And Innovation: Raised inflammatory markers were present in 39.68% of our patients. Whole body MRI is useful for diagnosis and also determining response to treatment. A greater number of lesions were detected on radiological imaging compared to clinical assessment. Metaphyses of long bones were most often involved and the distal tibial metaphyses (49.6%) were the most common site. Non-steroidal anti-inflammatory drugs were used as first line (81.67%) followed by bisphosphonates (61.79%). There was no difference in number of medications used for management in unifocal versus multifocal disease. TNF blockers were used with good effect in our cohort.
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http://dx.doi.org/10.1186/s12969-018-0290-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251121PMC
November 2018

JAK 1/2 Blockade in MDA5 Gain-of-Function.

J Clin Immunol 2018 11 15;38(8):844-846. Epub 2018 Nov 15.

Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.

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http://dx.doi.org/10.1007/s10875-018-0563-2DOI Listing
November 2018

Growth patterns in early juvenile idiopathic arthritis: Results from the Childhood Arthritis Prospective Study (CAPS).

Semin Arthritis Rheum 2018 08 7;48(1):53-60. Epub 2017 Nov 7.

Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, Division of Musculoskeletal & Dermatological Sciences. Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK; NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK. Electronic address:

Objectives: To investigate early vertical growth patterns and factors associated with poor growth in a modern inception cohort of UK children with juvenile idiopathic arthritis (JIA) using data from the Childhood Arthritis Prospective Study (CAPS).

Methods: A study period of 3 years was chosen. Children included in this analysis had a physician diagnosis of JIA and had height measurements available at both baseline and at 3-years of follow-up. Height is presented as z-scores calculated using World Health Organisation growth standards for age and gender. Growth over the 3-year period was assessed using change in z-score and height velocity. Univariable and multivariable linear regressions were used to identify factors associated with height z-score at baseline and change of height z-score at 3 years.

Results: 568 patients were included; 65% female, median baseline age 7.4 years [interquartile range (IQR) 3.6, 11.2], median symptom duration at presentation 5.5 months [IQR 3.1, 11.6]. Height z-score decreased significantly from baseline to 3 years (p ≤ 0.0001); baseline median height z-score was -0.02 (IQR -0.71, 0.61), decreasing to -0.47 (IQR -1.12, 0.24) at 3 years. Growth restriction, defined as change of height z-score ≤-0.5, was observed in 39% of patients. At 3 years, higher baseline height z-score was the strongest predictor for a negative change in height z-score [-0.3 per unit of baseline height z-score (95% CI: -0.36, -0.24), p < 0.0001].

Conclusions: Although overall height at 3 years after initial presentation to rheumatology is within the population norm, as a cohort, children with JIA experience a reduction of growth in height over the first 3 years of disease. Late presentation to paediatric rheumatology services is associated with lower height at presentation. However, patients with the lowest height z scores at presentation were also the most likely to see an improvement at 3 years. The impact of JIA on growth patterns is important to children and families and this study provides useful new data to support informed clinical care.
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http://dx.doi.org/10.1016/j.semarthrit.2017.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089842PMC
August 2018

Patterns of pain over time among children with juvenile idiopathic arthritis.

Arch Dis Child 2018 05 25;103(5):437-443. Epub 2017 Nov 25.

NIHR Manchester Musculoskeletal Biomedical Research Unit, Manchester Academic Health Science Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.

Objectives: Pain is a very common symptom of juvenile idiopathic arthritis (JIA). Disease activity alone cannot explain symptoms of pain in all children, suggesting other factors may be relevant. The objectives of this study were to describe the different patterns of pain experienced over time in children with JIA and to identify predictors of which children are likely to experience ongoing pain.

Methods: This study used longitudinal-data from patients (aged 1-16 years) with new-onset JIA. Baseline and up to 5-year follow-up pain data from the Childhood Arthritis Prospective Study (CAPS) were used. A two-step approach was adopted. First, pain trajectories were modelled using a discrete mixture model. Second, multinomial logistic regression was used to determine the association between variables and trajectories.

Results: Data from 851 individuals were included (4 years, median follow-up). A three-group trajectory model was identified: consistently low pain (n=453), improved pain (n=254) and consistently high pain (n=144). Children with improved pain or consistently high pain differed on average at baseline from consistently low pain. Older age at onset, poor function/disability and longer disease duration at baseline were associated with consistently high pain compared with consistently low pain. Early increases in pain and poor function/disability were also associated with consistently high pain compared with consistently low pain.

Conclusions: This study has identified routinely collected clinical factors, which may indicate those individuals with JIA at risk of poor pain outcomes earlier in disease. Identifying those at highest risk of poor pain outcomes at disease onset may enable targeted pain management strategies to be implemented early in disease thus reducing the risk of poor pain outcomes.
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http://dx.doi.org/10.1136/archdischild-2017-313337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916104PMC
May 2018

Development of a national audit tool for juvenile idiopathic arthritis: a BSPAR project funded by the Health Care Quality Improvement Partnership.

Rheumatology (Oxford) 2018 01;57(1):140-151

Paediatric Rheumatology, Alder Hey Children's Hospital, Liverpool, UK.

Objective: Timely access to holistic multidisciplinary care is the core principle underpinning management of juvenile idiopathic arthritis (JIA). Data collected in national clinical audit programmes fundamentally aim to improve health outcomes of disease, ensuring clinical care is equitable, safe and patient-centred. The aim of this study was to develop a tool for national audit of JIA in the UK.

Methods: A staged and consultative methodology was used across a broad group of relevant stakeholders to develop a national audit tool, with reference to pre-existing standards of care for JIA. The tool comprises key service delivery quality measures assessed against two aspects of impact, namely disease-related outcome measures and patient/carer reported outcome and experience measures.

Results: Eleven service-related quality measures were identified, including those that map to current standards for commissioning of JIA clinical services in the UK. The three-variable Juvenile Arthritis Disease Activity Score and presence/absence of sacro-iliitis in patients with enthesitis-related arthritis were identified as the primary disease-related outcome measures, with presence/absence of uveitis a secondary outcome. Novel patient/carer reported outcomes and patient/carer reported experience measures were developed and face validity confirmed by relevant patient/carer groups.

Conclusion: A tool for national audit of JIA has been developed with the aim of benchmarking current clinical practice and setting future standards and targets for improvement. Staged implementation of this national audit tool should facilitate investigation of variability in levels of care and drive quality improvement. This will require engagement from patients and carers, clinical teams and commissioners of JIA services.
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http://dx.doi.org/10.1093/rheumatology/kex322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850477PMC
January 2018

Deep brain stimulation of the anterior limb of the internal capsule for treatment of therapy-refractory obsessive compulsive disorder (OCD): a case study highlighting neurocognitive and psychiatric changes.

Neurocase 2017 Apr 1;23(2):138-145. Epub 2017 May 1.

b Department of Neurology , Baylor College of Medicine , Houston , TX , USA.

Obsessive compulsive disorder (OCD) is an anxiety disorder characterized by repeated, unwanted thoughts and behaviors. Individuals with this condition often experience significant emotional distress secondary to their symptoms. Additionally, impairments in attention/concentration, processing speed, and executive functions are typically observed. The exact pathology of OCD remains unknown; consequently, it can be difficult to treat patients with severe symptomatology. Deep brain stimulation (DBS) may be a viable treatment option for individuals who do not respond to medication and/or cognitive behavioral therapy. The following case discusses DBS of the anterior limb of the internal capsule for a patient with severe, therapy-refractory OCD, including pre- to postoperative neurocognitive and psychiatric changes.
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http://dx.doi.org/10.1080/13554794.2017.1319958DOI Listing
April 2017

2016 American College of Rheumatology/European League Against Rheumatism Criteria for Minimal, Moderate, and Major Clinical Response in Juvenile Dermatomyositis: An International Myositis Assessment and Clinical Studies Group/Paediatric Rheumatology International Trials Organisation Collaborative Initiative.

Ann Rheum Dis 2017 May;76(5):782-791

Istituto Giannina Gaslini, Pediatria II - Reumatologia, PRINTO, Genoa, Italy.

To develop response criteria for juvenile dermatomyositis (DM). We analysed the performance of 312 definitions that used core set measures from either the International Myositis Assessment and Clinical Studies Group (IMACS) or the Paediatric Rheumatology International Trials Organisation (PRINTO) and were derived from natural history data and a conjoint analysis survey. They were further validated using data from the PRINTO trial of prednisone alone compared to prednisone with methotrexate or cyclosporine and the Rituximab in Myositis (RIM) trial. At a consensus conference, experts considered 14 top candidate criteria based on their performance characteristics and clinical face validity, using nominal group technique. Consensus was reached for a conjoint analysis-based continuous model with a total improvement score of 0-100, using absolute per cent change in core set measures of minimal (≥30), moderate (≥45), and major (≥70) improvement. The same criteria were chosen for adult DM/polymyositis, with differing thresholds for improvement. The sensitivity and specificity were 89% and 91-98% for minimal improvement, 92-94% and 94-99% for moderate improvement, and 91-98% and 85-86% for major improvement, respectively, in juvenile DM patient cohorts using the IMACS and PRINTO core set measures. These criteria were validated in the PRINTO trial for differentiating between treatment arms for minimal and moderate improvement (p=0.009-0.057) and in the RIM trial for significantly differentiating the physician's rating for improvement (p<0.006). The response criteria for juvenile DM consisted of a conjoint analysis-based model using a continuous improvement score based on absolute per cent change in core set measures, with thresholds for minimal, moderate, and major improvement.
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http://dx.doi.org/10.1136/annrheumdis-2017-211401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5517365PMC
May 2017

2016 American College of Rheumatology/European League Against Rheumatism Criteria for Minimal, Moderate, and Major Clinical Response in Juvenile Dermatomyositis: An International Myositis Assessment and Clinical Studies Group/Paediatric Rheumatology International Trials Organisation Collaborative Initiative.

Arthritis Rheumatol 2017 05 6;69(5):911-923. Epub 2017 Apr 6.

Istituto Giannina Gaslini, Pediatria II - Reumatologia, PRINTO, Genoa, Italy.

Objective: To develop response criteria for juvenile dermatomyositis (DM).

Methods: We analyzed the performance of 312 definitions that used core set measures from either the International Myositis Assessment and Clinical Studies Group (IMACS) or the Paediatric Rheumatology International Trials Organisation (PRINTO) and were derived from natural history data and a conjoint analysis survey. They were further validated using data from the PRINTO trial of prednisone alone compared to prednisone with methotrexate or cyclosporine and the Rituximab in Myositis (RIM) trial. At a consensus conference, experts considered 14 top candidate criteria based on their performance characteristics and clinical face validity, using nominal group technique.

Results: Consensus was reached for a conjoint analysis-based continuous model with a total improvement score of 0-100, using absolute percent change in core set measures of minimal (≥30), moderate (≥45), and major (≥70) improvement. The same criteria were chosen for adult DM/polymyositis, with differing thresholds for improvement. The sensitivity and specificity were 89% and 91-98% for minimal improvement, 92-94% and 94-99% for moderate improvement, and 91-98% and 85-86% for major improvement, respectively, in juvenile DM patient cohorts using the IMACS and PRINTO core set measures. These criteria were validated in the PRINTO trial for differentiating between treatment arms for minimal and moderate improvement (P = 0.009-0.057) and in the RIM trial for significantly differentiating the physician's rating for improvement (P < 0.006).

Conclusion: The response criteria for juvenile DM consisted of a conjoint analysis-based model using a continuous improvement score based on absolute percent change in core set measures, with thresholds for minimal, moderate, and major improvement.
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http://dx.doi.org/10.1002/art.40060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577002PMC
May 2017

Treatment prescribing patterns in patients with juvenile idiopathic arthritis (JIA): Analysis from the UK Childhood Arthritis Prospective Study (CAPS).

Semin Arthritis Rheum 2016 10 8;46(2):190-195. Epub 2016 Jun 8.

Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK; NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University, Hospitals NHS Foundation Trust and University of Manchester Partnership, Manchester, UK. Electronic address:

Objective: Initial treatment of juvenile idiopathic arthritis (JIA) is largely based on the extent of joint involvement, disease severity and ILAR category. The licensing of biologic therapies for JIA has expanded treatment options. The aims of the study are (1) to describe treatment prescribing patterns in JIA over the first 3 years following first presentation to paediatric rheumatology and (2) to determine whether patterns of treatment have changed as biologics have become more widely available.

Methods: Children with at least 3 years of follow-up within the Childhood Arthritis Prospective Study (CAPS) were included. For analysis, children were placed into one of five groups according to their initial presentation to paediatric rheumatology: oligoarthritis (oJIA), polyarthritis (pJIA), systemic (sJIA), enthesitis-related arthritis (ERA) and psoriatic arthritis (PsA). Treatment patterns over 3 years were described.

Results: Of 1051 children, 58% received synthetic disease-modifying anti-rheumatic drugs (sDMARD) and 20% received biologics over the 3 years. Use of sDMARDs and biologics was higher in more severe disease presentations (sJIA and pJIA); however, 35% and 10% who presented with oJIA were also treated with sDMARDs and biologics, respectively. The number of children receiving sDMARD after 2006 was higher (p = 0.02); however, there was no difference in biologic prescribing before and after 2006 (p = 0.4).

Conclusions: A high proportion of children presenting with JIA received sDMARDs plus/minus biologics during 3 years of follow-up. This was most common for patients with severe JIA but was also prescribed for patients with oligoarticular disease, despite the lack of evidence for effectiveness in this category.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052142PMC
http://dx.doi.org/10.1016/j.semarthrit.2016.06.001DOI Listing
October 2016

Trends in paediatric rheumatology referral times and disease activity indices over a ten-year period among children and young people with Juvenile Idiopathic Arthritis: results from the childhood arthritis prospective Study.

Rheumatology (Oxford) 2016 07 25;55(7):1225-34. Epub 2016 Mar 25.

Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, Institute for Inflammation and Repair, Faculty of Medical and Human Sciences, University of Manchester, Manchester, NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK

Objectives: The medical management of JIA has advanced significantly over the past 10 years. It is not known whether these changes have impacted on outcomes. The aim of this analysis was to identify and describe trends in referral times, treatment times and 1-year outcomes over a 10-year period among children with JIA enrolled in the Childhood Arthritis Prospective Study.

Methods: The Childhood Arthritis Prospective Study is a prospective inception cohort of children with new-onset inflammatory arthritis. Analysis included all children recruited in 2001-11 with at least 1 year of follow-up, divided into four groups by year of diagnosis. Median referral time, baseline disease pattern (oligoarticular, polyarticular or systemic onset) and time to first definitive treatment were compared between groups. Where possible, clinical juvenile arthritis disease activity score (cJADAS) cut-offs were applied at 1 year.

Results: One thousand and sixty-six children were included in the analysis. The median time from symptom onset and referral to first paediatric rheumatology appointment (22.7-24.7 and 3.4-4.7 weeks, respectively) did not vary significantly (∼20% seen within 10 weeks of onset and ∼50% within 4 weeks of referral). For oligoarticular and polyarticular disease, 33.8-47 and 25.4-34.9%, respectively, achieved inactive disease by 1 year, with ∼30% in high disease activity at 1 year. A positive trend towards earlier definitive treatment reached significance in oligoarticular and polyarticular pattern disease.

Conclusion: Children with new-onset JIA have a persistent delay in access to paediatric rheumatology care, with one-third in high disease activity at 1 year and no significant improvement over the past 10 years. Contributing factors may include service pressures and poor awareness. Further research is necessary to gain a better understanding and improve important clinical outcomes.
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http://dx.doi.org/10.1093/rheumatology/kew021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911538PMC
July 2016

Influence of past breast feeding on pattern and severity of presentation of juvenile idiopathic arthritis.

Arch Dis Child 2016 Apr 14;101(4):348-51. Epub 2015 Sep 14.

Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK.

This analysis aimed to study the influence of breast feeding on the pattern and severity of juvenile idiopathic arthritis (JIA) at presentation. The association between ever versus never breast feeding and disease severity at onset was compared in 923 children with JIA recruited to the UK Childhood Arthritis Prospective Study at first presentation to rheumatology. Fifty six per cent of children were ever breast fed (median 3.7 months). Breastfed children reported a lower median age at onset, a lower Childhood Health Assessment Questionnaire (CHAQ), a measure of disease severity, lower parent general evaluation scores and lower pain at presentation. There was a trend towards a higher proportion of breastfed children with rheumatoid factor-negative polyarthritis, but lesser enthesitis-related and psoriatic arthritis. There was a statistically significant inverse association between breast feeding and high CHAQ, even after adjusting for differences in socioeconomic status (adjusted OR 0.61 (95% CI 0.39 to 0.95)). Further work to understand the reasons behind these associations is required.
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http://dx.doi.org/10.1136/archdischild-2014-308117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819639PMC
April 2016

Transitional care in clinical networks for young people with juvenile idiopathic arthritis: current situation and challenges.

Clin Rheumatol 2016 Apr 30;35(4):893-9. Epub 2015 Apr 30.

Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK.

Clinical networks for paediatric and adolescent rheumatology are evolving, and their effect and role in the transition process between paediatric and adult services are unknown. We therefore explored the experiences of those involved to try and understand this further. Health professionals, young people with juvenile idiopathic arthritis and their families were recruited via five national health service paediatric and adolescent rheumatology specialist centres and networks across the UK. Seventy participants took part in focus groups and one-to-one interviews. Data was analysed using coding, memoing and mapping techniques to identify features of transitional services across the sector. Variation and inequities in transitional care exist. Although transition services in networks are evolving, development has lagged behind other areas with network establishment focusing more on access to paediatric rheumatology multidisciplinary teams. Challenges include workforce shortfalls, differences in service priorities, standards and healthcare infrastructures, and managing the legacy of historic encounters. Providing equitable high-quality clinically effective services for transition across the UK has a long way to go. There is a call from within the sector for more protected time, staff and resources to develop transition roles and services, as well as streamlining of local referral pathways between paediatric and adult healthcare services. In addition, there is a need to support professionals in developing their understanding of transitional care in clinical networks, particularly around service design, organisational change and the interpersonal skills required for collaborative working. Key messages • Transitional care in clinical networks requires collaborative working and an effective interface with paediatric and adult rheumatology.• Professional centrism and historic encounters may affect collaborative relationships within clinical networks.• Education programmes need to support the development of interpersonal skills and change management, to facilitate professionals in networks delivering transitional care.
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http://dx.doi.org/10.1007/s10067-015-2950-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819554PMC
April 2016

The association between low socioeconomic status with high physical limitations and low illness self-perception in patients with juvenile idiopathic arthritis: results from the Childhood Arthritis Prospective Study.

Arthritis Care Res (Hoboken) 2015 Mar;67(3):382-9

Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.

Objective: To examine the association between socioeconomic status (SES) and delay to a pediatric rheumatology clinic, disease severity, and illness perception in patients with juvenile idiopathic arthritis in England.

Methods: Using the Index of Multiple Deprivation, 923 consecutive children from the Childhood Arthritis Prospective Study were assigned to SES groups: high-SES (19.1%), middle-SES (44.5%), or low-SES (36.4%). At baseline, disease activity was assessed, and the Childhood Health Assessment Questionnaire (C-HAQ), the Illness Perception Questionnaire, and the Child Health Questionnaire, version Parent Form 50, were completed. Linear median regression analyses or zero-inflated negative binominal (ZINB) regression analyses were used.

Results: Delay to first pediatric rheumatology consultation was the same between the 3 SES groups. Although disease activity scores assessed by the pediatric rheumatologist did not differ between the 3 SES groups, persons in the low-SES group recorded higher C-HAQ scores compared to the high-SES group (zero-inflated part of ZINB odds ratio 0.28 [95% confidence interval (95% CI) 0.14, 0.55], count part of ZINB β 0.26 [95% CI 0.05, 0.48]). Parents with low SES also reported more often that their children's school work or activities with friends had been limited. Furthermore, the low-SES group had a worse perception about the consequences of the disease and the effect of treatment than those in the high-SES group.

Conclusion: Patients from a low-SES background report more problems with daily activities and have a lower perception of the consequences of the disease than patients from a high-SES background, warranting special attention from a multidisciplinary team.
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http://dx.doi.org/10.1002/acr.22466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737227PMC
March 2015

Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling.

Nat Genet 2014 May 30;46(5):503-509. Epub 2014 Mar 30.

Centre de Génétique, Hôpital d'Enfants, CHU de Dijon et Université de Bourgogne, Dijon, France.

The type I interferon system is integral to human antiviral immunity. However, inappropriate stimulation or defective negative regulation of this system can lead to inflammatory disease. We sought to determine the molecular basis of genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome and of other undefined neurological and immunological phenotypes also demonstrating an upregulated type I interferon response. We found that heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (also called MDA5) cause a spectrum of neuroimmunological features consistently associated with an enhanced interferon state. Cellular and biochemical assays indicate that these mutations confer gain of function such that mutant IFIH1 binds RNA more avidly, leading to increased baseline and ligand-induced interferon signaling. Our results demonstrate that aberrant sensing of nucleic acids can cause immune upregulation.
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http://dx.doi.org/10.1038/ng.2933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4004585PMC
May 2014

Foot orthoses in children with juvenile idiopathic arthritis: a randomised controlled trial.

Arch Dis Child 2014 Jul 17;99(7):649-51. Epub 2014 Mar 17.

Introduction: There is limited evidence supporting the podiatric treatment of children with juvenile idiopathic arthritis (JIA). This multicentre randomised controlled trial aimed to determine whether preformed foot orthoses (FOs) impacted on pain and quality of life (QoL) in children with JIA.

Methods: Eligible children were randomised to receive either 'fitted' FOs with customised chair-side corrections or 'control' FOs made without corrections. Changes in pain and QoL were measured using a visual analogue scale and Paediatric Quality of Life questionnaire, respectively. JIA children were assessed at baseline, 3 months and 6 months.

Results: 60 children were recruited. 179 out of a possible 180 assessments (99.4%) were completed. A statistically significant greater difference in pain reduction (baseline - 6 months) was seen between the two groups favouring fitted FOs (p=0.029). The reduction in pain in the fitted FOs group was clinically important (8 mm). Significant differences in QoL favouring fitted FOs were also identified as measured by the children and independently by their parents/carers.

Conclusions: Fitted FOs may reduce pain and improve QoL in selected children with JIA.

Trial Registration Number: NCT02001844.
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http://dx.doi.org/10.1136/archdischild-2013-305166DOI Listing
July 2014

Validity of a three-variable Juvenile Arthritis Disease Activity Score in children with new-onset juvenile idiopathic arthritis.

Ann Rheum Dis 2013 Dec 20;72(12):1983-8. Epub 2012 Dec 20.

Arthritis Research UK Epidemiology Unit, University of Manchester, , Manchester, UK.

Objectives: To investigate the validity and feasibility of the Juvenile Arthritis Disease Activity Score (JADAS) in the routine clinical setting for all juvenile idiopathic arthritis (JIA) disease categories and explore whether exclusion of the erythrocyte sedimentation rate (ESR) from JADAS (the 'JADAS3') influences correlation with single markers of disease activity.

Methods: JADAS-71, JADAS-27 and JADAS-10 were determined at baseline for an inception cohort of children with JIA in the Childhood Arthritis Prospective Study. JADAS3-71, JADAS3-27 and JADAS3-10 were determined using an identical formula but with exclusion of ESR. Correlation of JADAS with JADAS3 and single measures of disease activity/severity were determined by category.

Results: Of 956 eligible children, sufficient data were available to calculate JADAS-71, JADAS-27 and JADAS-10 at baseline in 352 (37%) and JADAS3 in 551 (58%). The median (IQR) JADAS-71, JADAS-27 and JADAS-10 for all 352 children was 11 (5.9-18), 10.4 (5.7-17) and 11 (5.9-17.3), respectively. Median JADAS and JADAS3 varied significantly with the category (Kruskal-Wallis p=0.0001), with the highest values in children with polyarticular disease patterns. Correlation of JADAS and JADAS3 across all categories was excellent. Correlation of JADAS71 with single markers of disease activity/severity was good to moderate, with some variation across the categories. With the exception of ESR, correlation of JADAS3-71 was similar to correlation of JADAS-71 with the same indices.

Conclusions: This study is the first to apply JADAS to all categories of JIA in a routine clinical setting in the UK, adding further information about the feasibility and construct validity of JADAS. For the majority of categories, clinical applicability would be improved by exclusion of the ESR.
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http://dx.doi.org/10.1136/annrheumdis-2012-202031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3841758PMC
December 2013

Access to care for children and young people diagnosed with localized scleroderma or juvenile SSc in the UK.

Rheumatology (Oxford) 2012 Jul 16;51(7):1235-9. Epub 2012 Feb 16.

Department of Paediatric Rheumatology, Sheffield Children's Hospital, Western Bank, Sheffield S10 2TH, UK.

Objectives: To describe pathways of care and referral to paediatric rheumatology from onset of first symptom (noticed by the patient or their family) to diagnosis for children and young people diagnosed with localized scleroderma (LS) or juvenile SSc (jSSc).

Methods: Retrospective case note audit of patients under paediatric rheumatology care who presented during January 2005-January 2010. Data included disease subtype, sex, age at key points in the referral pathway and health care professional (HCP) contact. All patient and HCP data were pseudo-anonymized in accordance with good clinical practice.

Results: Data were from eight UK centres that saw 89 cases: 62 females, 26 males; 73 LS, 16 jSSc. Median time from first symptom to first HCP review was 4 (range 0-72) months (LS) and 1 (range 0-50) month (jSSc). Median time from first symptom to paediatric rheumatology review was 15 (range 1-103) months (LS) and 7 (range 0-50) months (jSSc). Median time from first HCP review to first paediatric rheumatology review was 11 (range 0-103) months (LS) and 2 (range 0-10) months. First HCP seen (74%) was usually a general practitioner. The referring HCP to paediatric rheumatology was usually a dermatologist (56%) for LS. Median time from first symptom to diagnosis was 13 (range 1-102) months (LS) and 8 (range 1-50) months (jSSc).

Conclusion: A prolonged interval occurs from first symptom to definitive diagnosis, which may adversely affect outcome. There is a need to raise awareness of this rare diagnosis and facilitate earlier recognition.
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http://dx.doi.org/10.1093/rheumatology/ker521DOI Listing
July 2012

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

Rheumatology (Oxford) 2011 Jan 3;50(1):189-95. Epub 2010 Nov 3.

Department of Paediatric Rheumatology, Institute of Child Health, 4th Floor Laboratories Block, Birmingham Children's Hospital-NHS Foundation Trust, University of Birmingham, Whittall Street, Birmingham, B4 6NH, UK.

Objective: Since 2004, juvenile idiopathic arthritis (JIA) patients treated with etanercept and/or MTX have been monitored in the British Society for Paediatric and Adolescent Rheumatology Biologics and New Drug Register. Here, we report the duration of etanercept use for the first 5 years of the register and reasons for discontinuation.

Methods: Disease subtype and activity, comorbidity, treatment efficacy and safety data were recorded. Etanercept discontinuation was defined as stopping the drug because of disease remission or treatment failure. Time to discontinuation was explored using Kaplan-Meier survival analysis with remaining patients censored at 5-year follow-up.

Results: A total of 483 etanercept-treated JIA patients were enrolled from 30 UK centres, representing 941 patient-years of follow-up. A total of 100 (20.7%) patients discontinued etanercept; 9 due to disease control, 88 because of treatment failure, 2 for unknown reasons and 1 because of a change in diagnosis. Of the 53 patients in whom etanercept was perceived to be ineffective at controlling the inflammation, 48 were prescribed other biologic drugs [26/48 (54%) infliximab]. In 21 patients with intolerance, infections, CNS events and a few isolated events were associated with discontinuation. Using Kaplan-Meier analysis, at 5 years 69% (95% CI 61, 77%) had not experienced treatment failure. Discontinuation of etanercept for inefficacy was associated with systemic arthritis subtype [odds ratio (OR) 2.55, 95% CI 1.27, 5.14], chronic anterior uveitis (OR 2.39, 95% CI 1.06, 5.35) and inefficacy of MTX before starting etanercept (OR 8.3, 95% CI 1.14, 60.58).

Conclusions: In a cohort of JIA patients treated with etanercept and followed for a median of 2 years (maximum 5 years), the majority (69%) remain on the drug.
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http://dx.doi.org/10.1093/rheumatology/keq308DOI Listing
January 2011

A national registry for juvenile dermatomyositis and other paediatric idiopathic inflammatory myopathies: 10 years' experience; the Juvenile Dermatomyositis National (UK and Ireland) Cohort Biomarker Study and Repository for Idiopathic Inflammatory Myopathies.

Rheumatology (Oxford) 2011 Jan 7;50(1):137-45. Epub 2010 Sep 7.

Rheumatology Unit, UCL Institute of Child Health, Great Ormond Street Hospital, 30 Guilford Street, University College London, London WC1N 1EH, UK.

Objectives: The paediatric idiopathic inflammatory myopathies (IIMs) are a group of rare chronic inflammatory disorders of childhood, affecting muscle, skin and other organs. There is a severe lack of evidence base for current treatment protocols in juvenile myositis. The rarity of these conditions means that multicentre collaboration is vital to facilitate studies of pathogenesis, treatment and disease outcomes. We have established a national registry and repository for childhood IIM, which aims to improve knowledge, facilitate research and clinical trials, and ultimately to improve outcomes for these patients.

Methods: A UK-wide network of centres and research group was established to contribute to the study. Standardized patient assessment, data collection forms and sample protocols were agreed. The Biobank includes collection of peripheral blood mononuclear cells, serum, genomic DNA and biopsy material. An independent steering committee was established to oversee the use of data/samples. Centre training was provided for patient assessment, data collection and entry.

Results: Ten years after inception, the study has recruited 285 children, of which 258 have JDM or juvenile PM; 86% of the cases have contributed the biological samples. Serial sampling linked directly to the clinical database makes this a highly valuable resource. The study has been a platform for 20 sub-studies and attracted considerable funding support. Assessment of children with myositis in contributing centres has changed through participation in this study.

Conclusions: This establishment of a multicentre registry and Biobank has facilitated research and contributed to progress in the management of a complex group of rare muscloskeletal conditions.
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http://dx.doi.org/10.1093/rheumatology/keq261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2999955PMC
January 2011

A randomized comparative trial of generalized vs targeted physiotherapy in the management of childhood hypermobility.

Rheumatology (Oxford) 2010 Feb 30;49(2):315-25. Epub 2009 Nov 30.

Department of Paediatric Rheumatology, Alder Hey Children's Hospital NHS Foundation Trust, Liverpool, UK.

Objective: Joint hypermobility, common in childhood, can be associated with severe pain and significant morbidity. Physiotherapy, the mainstay of treatment, lacks a robust evidence base. This study is aimed at determining the best physiotherapy intervention in managing childhood hypermobility.

Methods: A prospective randomized comparative trial (RCT) compared a 6-week generalized programme, improving muscular strength and fitness, with a targeted programme aimed at correcting motion control of symptomatic joints. Patients were assessed on symptom scores (pain/global-impact), function, muscle strength and fitness.

Results: Fifty-seven children, aged 7-16 years with symptomatic hypermobility, were randomly assign to receive a targeted (T; n = 30) or generalized (G; n = 27) programme. Statistically significant improvements were demonstrated in both the children's and parental pain scores across both the randomized groups between baseline and follow-up assessments (P < 0.05). However, the difference in improvement between the groups was not statistically significant. Child's assessment of change in pain score: mean difference (95% CI) T - G, 3.97 (-15.59, 20.85) at the end of treatment and 9.41 at 3-month follow-up (-17.42, 36.24). At the end of treatment, parental assessment of change in pain score, T - G was: -0.27 (-15.05, 14.50) and at 3-month follow-up it was: -9.48 (-26.40, 7.43). Change in parental global assessment was statistically significant, in favour of targeted physiotherapy at final assessment: -21.29 (-40.03, -2.55).

Conclusion: This is the first physiotherapy RCT for treating hypermobility. It demonstrated significant and sustained reduction in pain when both groups were combined, but did not detect any difference between the groups. This study provides normative and methodological data for future studies of hypermobility.

Trial Registration: Current Controlled Trials, www.controlled-trials.com, ISRCTN58523390.
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http://dx.doi.org/10.1093/rheumatology/kep362DOI Listing
February 2010

HLA-DPB1 associations differ between DRB1*03 positive anti-Jo-1 and anti-PM-Scl antibody positive idiopathic inflammatory myopathy.

Rheumatology (Oxford) 2009 Oct 18;48(10):1213-7. Epub 2009 Aug 18.

Centre for Integrated Genomic Medical Research, University of Manchester, UK.

Objective: The HLA 8.1 ancestral haplotype (HLA-B*08/DRB1*03/DQA1*05/DQB1*02) is associated with adult/juvenile idiopathic inflammatory myopathy (IIM), but confers a greater strength of association in patients possessing anti-Jo-1 or anti-PM-Scl antibodies. The HLA-DPB1 gene is centromeric to other HLA class II loci and separated by a recombination hotspot. We investigated whether HLA-DPB1 associations differ between anti-Jo-1 and anti-PM-Scl antibody-positive IIM cases.

Methods: Two hundred and thirty-three adult IIM patients (73% females, 49.4 +/- 13.6 years) with PM (n = 89), DM (n = 88) and myositis associated with another CTD (n = 55) and 85 juvenile DM patients (75% females, 6.2 +/- 3.6 years) were compared with 678 UK Caucasian controls. Patients/controls were genotyped for HLA-DPB1 and DRB1 alleles. Myositis-specific and associated antibodies were identified in cases using immunoprecipitation.

Results: HLA-DPB1*0101 was associated with IIM overall [22 vs 13% controls, corrected probability (P(corr)) = 2 x 10(-03); odds ratio (OR) 2.0; 95% CI 1.4, 2.9], PM (P(corr) = 7 x 10(-03); OR 2.5; 95% CI 1.5, 4.4) and anti-Jo-1 (P(corr) = 3 x 10(-5); OR 4.1; 95% CI 2.1, 7.8). No significant DPB1*0101 difference was present between anti-PM-Scl cases and controls. The HLA-DPB1*0101 association in IIM overall cases was dependent on the presence of DRB1*03. A number of HLA-DRB1*03/DPB1 haplotypes were identified, but only DRB1*03/DPB1*0101 was associated with anti-Jo-1 antibody-positive cases.

Conclusions: The HLA-DRB1*03/DPB1*0101 haplotype is a risk factor for anti-Jo-1 antibody-positive IIM. Thus, although DRB1*03 is strongly associated with possession of either anti-Jo-1 or anti-PM-Scl, differing antibody associations are observed at the HLA-DPB1 locus.
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http://dx.doi.org/10.1093/rheumatology/kep248DOI Listing
October 2009

Shape analysis of 123I-N-omega-fluoropropyl-2-beta-carbomethoxy-3beta-(4-iodophenyl) nortropane single-photon emission computed tomography images in the assessment of patients with parkinsonian syndromes.

Nucl Med Commun 2009 Mar;30(3):194-201

Medical Physics, Aberdeen Royal Infirmary, NHS-Grampian, University of Aberdeen, UK.

Purpose: The purpose of this study was to show the viability and performance of a shape-based pattern recognition technique applied to I-N-omega-fluoropropyl-2-beta-carbomethoxy-3beta-(4-iodophenyl) nortropane single-photon emission computed tomography (FP-CIT SPECT) in patients with parkinsonism.

Methods: A fully automated pattern recognition tool, based on the shape of FP-CIT SPECT images, was written using Java. Its performance was evaluated and compared with QuantiSPECT, a region-of-interest-based quantitation tool, and observer performance using receiver operating characteristic analysis and kappa statistics. The techniques were compared using a sample of patients and controls recruited from a prospective community-based study of first presentation of parkinsonian symptoms with longitudinal follow up (median 3 years).

Results: The shape-based technique as well as the conventional semiquantitative approach was performed by experienced observers. The technique had a high level of automation, thereby avoiding observer/operator variability.

Conclusion: A pattern recognition approach is a viable alternative to traditional methods of analysis in FP-CIT SPECT and has additional advantages.
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http://dx.doi.org/10.1097/MNM.0b013e328314b863DOI Listing
March 2009

Treatment outcome for adolescent obsessive-compulsive disorder in a specialized hospital setting.

J Psychiatr Pract 2008 May;14(3):137-45

The Menninger Clinic and Baylor College of Medicine, Houston, TX 77080, USA.

Although few data are available concerning adolescents with obsessive-compulsive disorder (OCD), the existing literature suggests that cognitive-behavioral therapy (CBT) is the first-line treatment of choice for adolescents with mild to moderate OCD. A combination of CBT and serotonin reuptake inhibitors (SRIs) is recommended for more severe forms of OCD, based on the Expert Consensus Guidelines for the Treatment of Obsessive-Compulsive Disorder and the Pediatric OCD Treatment Study (POTS). Despite the effectiveness of CBT, a recent meta-analysis found that 27% of adolescent outpatients fail to show clinically significant improvement following CBT and many also fail to show improvement with pharmacotherapy. One alternative for those who do not improve with outpatient treatment is an intensive inpatient program. Within the last 10 years, two specialty hospitals have created programs that provide intensive CBT milieu treatment with multidisciplinary support (e.g., nursing, psychopharmacology) to treat adolescents with OCD. This naturalistic study describes treatment outcomes in 23 patients who received treatment in one of these programs between 2005 and 2006. Results suggest significant improvements on the majority of outcome measures, with 70% of the patients judged to meet criteria for clinically significant change. Thus, inpatient treatment appears potentially efficacious, although future controlled trials with larger samples are needed.
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http://dx.doi.org/10.1097/01.pra.0000320112.36648.3eDOI Listing
May 2008

Tufting enteropathy and skeletal dysplasia: is there a link?

Eur J Pediatr 2007 Mar 10;166(3):265-8. Epub 2006 Aug 10.

Gastroenterology Unit, Royal Liverpool Children's NHS Trust, Alder Hey, Eaton Road, Liverpool, L12 2AP, UK.

Introduction: Tufting enteropathy (intestinal epithelial dysplasia), a rare congenital enteropathy, presents in the first few months of life with chronic watery diarrhoea and impaired growth. The molecular basis for this condition is not known. We report our experience with a case of tufting enteropathy that developed an unusual skeletal dysplasia with an abnormal blood picture. After extensive investigations including repeated gastrointestinal endoscopies and biopsies, the diagnosis of tufting enteropathy was made. During the third year of her life, the patient's height was static. A full skeletal survey was performed and demonstrated features of generalised skeletal dysplasia, some of them consistent with those of parastremmatic dwarfism. At the age of five years, she developed Coomb's positive haemolytic anaemia and thrombocytopenia with a negative auto-antibody screen including anti-enterocyte antibodies.

Conclusion: There might be generalised matrix (including cartilage matrix protein), basement membrane abnormalities or both. A secondary protein leak might occur in the intestine with autosensitisation and development of autoimmune phenomena. More molecular research is needed to identify a possible link.
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http://dx.doi.org/10.1007/s00431-006-0231-zDOI Listing
March 2007

Adolescent development and SLE.

Best Pract Res Clin Rheumatol 2006 Apr;20(2):353-68

Department of Rheumatology, Royal Liverpool Children's Hospital, Liverpool L1 2 2AP, UK.

Adolescence is a time of profound biological and psychosocial change. The management of a complex chronic condition such as systemic lupus erythematosus (SLE) during this period is a challenging but rewarding task for the clinician. Early diagnosis and optimal disease control is essential in order to facilitate normal adolescent development and minimize long-term disease sequelae. Current treatment regimens are associated with significant toxicity in young people, and there is a need for new, less toxic regimens. There are currently no controlled therapeutic studies in adolescents with SLE. Those involved in the care of these young people must ensure that they have appropriate access to specialist medical services while ensuring that their specific needs as adolescents in the health-care system are addressed.
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http://dx.doi.org/10.1016/j.berh.2005.11.003DOI Listing
April 2006

So doctor, what exactly is wrong with my muscles? Glutaric aciduria type II presenting in a teenager.

Neuromuscul Disord 2006 Apr 9;16(4):269-73. Epub 2006 Mar 9.

Department of Rheumatology, Royal Liverpool Children's NHS Trust, Eaton Road, L12 2AP, Liverpool, UK.

Late-onset glutaric aciduria type II (GAII) is a rare but treatable cause of profound proximal myopathy. GAII is caused by defects in intra-mitochondrial acyl-CoA dehydrogenation due to deficiency in one of three molecules: the alpha or beta subunits of the electron transport flavoprotein (ETFA; OMIM 231680, ETFB; OMIM 130410), or ETF-dehydrogenase (ETFDH; OMIM 231675). This case report illustrates that GAII may present in the teenage years and may not be associated with hypoglycaemia. It outlines some important diagnostic conundrums faced in diagnosing and managing juvenile onset myopathies. Mutational analysis from this patient revealed two mutations of the ETF-DH gene: EFTDH-334C>T/His122Tyr and EFTDH-1366C>A/Pro456Thr (OMIM 231675). An outline of this rare but important disease, its clinical characteristics and diagnostic methodology are given.
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http://dx.doi.org/10.1016/j.nmd.2006.01.001DOI Listing
April 2006
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