When flexibility is not necessarily a virtue: a review of hypermobility syndromes and chronic or recurrent musculoskeletal pain in children

Chronic or recurrent musculoskeletal pain is a common complaint in children. Among the most common causes for this problem are different conditions associated with hypermobility. Pediatricians and allied professionals should be well aware of the characteristics of the different syndromes associated with hypermobility and facilitate early recognition and appropriate management. In this review we provide information on Benign Joint Hypermobility Syndrome, Ehlers-Danlos Syndrome, Marfan Syndrome, Loeys-Dietz syndrome and Stickler syndrome, and discuss their characteristics and clinical management

The Hindi version of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR)

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient-reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Hindi language. The reading comprehension of the questionnaire was tested in ten JIA parents and patients. Each participating centre was asked to collect demographic, clinical data and the JAMAR in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the three Likert assumptions, floor/ceiling effects, internal consistency, Cronbach\u2019s alpha, interscale correlations, test\u2013retest reliability, and construct validity (convergent and discriminant validity). A total of 275 JIA patients (28.4% systemic, 10.9% oligoarticular, 13.8% RF negative polyarthritis, 46.9% other categories) and 98 healthy children were enrolled in three centres. The JAMAR components discriminated well healthy subjects from JIA patients. Notably, there is no significant difference between the healthy subjects and their affected peers in the school-related problems variable. All JAMAR components revealed good psychometric performances. In conclusion, the Hindi version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and clinical research

Personal non-commercial use only

ABSTRACT. Objective. To put forward a new concept -Blau arteritis, a form of large-vessel vasculitis phenotypically related to Takayasu disease but genetically and clinically part of an expanded phenotype of Blau syndrome. Methods. We provide a clinical description of a new case and summarize previously published cases of arteritis associated with Blau syndrome. Genetic testing was performed by direct sequencing of exon 4 of the NOD2 gene. Results. The case described and those reviewed from the literature demonstrate the emerging phenotype of Takayasu-like arteritis in patients with Blau syndrome. Although most patients described to date depict an otherwise classic Blau syndrome phenotype, the current case was atypical in that the predominant features were arteritic. A novel substitution, G464W, in a highly conserved position near the nucleotide oligomerization domain of the NOD2 protein is also described. Blau syndrome is a monogenic granulomatous disease characterized in its most typical form by a triad of exuberant polyarthritis, uveitis, and granulomatous dermatitis 1 . It is caused by single amino acid substitutions at or near the NACHT domain of NOD2 2 . Although its systemic expression is well recognized after the descriptions of the expanded phenotype of Blau syndrome 3,4 , large-vessel vasculitis remains one of its serious and yet underrecognized manifestations if not actively sought by the treating physician. We describe an 8-year-old girl with symptomatic Takayasu-like arteritis and cardiomyopathy against the background of Blau syndrome with a G464W substitution in NOD2. We reported a similar case in 1989 5 , while others have observed arteritis among children with both sporadic and familial Blau phenotype before the mutation was known MATERIALS AND METHODS A girl, now 11 years old, from rural India, presented to us for the first time at 18 months of age, with bilateral knee effusions of a few months' duration in the absence of rash, uveitis, or systemic features. From the age of 1 month she had had recurrent and unexplained episodes of fever. Her antinuclear antibody result was negative. With a working diagnosis of oligoarticular juvenile arthritis she was administered intraarticular steroids, to which she responded well. She was lost to followup for almost 6 years thereafter. At the age of 8 years, she presented with gradually progressive dyspnea and palpitations of 3 months' duration. She had not thrived, and at this stage she weighed 17.2 kg and her height was 113 cm. There were no systemic features but joint examination showed "boggy synovitis" of the right elbow and knee. Cardiovascular examination showed an irregular pulse with a pulsatile precordium and evidence of congestive heart failure. A rhythm strip on electrocardiography showed ventricular extra beats. The echocardiogram revealed dilated ventricles, generalized hypokinesia with an ejection fraction of 20%, mild tricuspid and aortic regurgitation, and abnormal echogenicity within the wall of the left ventricle. With oligoarticular arthritis in a setting of dilated cardiomyopathy, elevated erythrocyte sedimentation rate, and family history of recurrent unexplained fevers in her mother, a diagnosis of early-onset sarcoidosis was considered. Her eye examination continued to be normal and all biopsies requiring sedation were deferred because of poor cardiac function. Oral methotrexate 10 mg/m 2 and corticosteroids 2 mg/kg were initiated in addition to decongestive treatment consisting of digitalis, diuretics, and captopril. She showed a gradual but steady improvement in effort tolerance, although her ejection fraction on electrocardiography did not mirror her clinical improvement. One and a half years later on a routine followup she was found to be hypertensive. Her carotid pulsations were decreased and a renal bruit was detected. Antihypertensive treatment was instituted and a compute

Personal non-commercial use only

ABSTRACT. Objective. To put forward a new concept -Blau arteritis, a form of large-vessel vasculitis phenotypically related to Takayasu disease but genetically and clinically part of an expanded phenotype of Blau syndrome. Methods. We provide a clinical description of a new case and summarize previously published cases of arteritis associated with Blau syndrome. Genetic testing was performed by direct sequencing of exon 4 of the NOD2 gene. Results. The case described and those reviewed from the literature demonstrate the emerging phenotype of Takayasu-like arteritis in patients with Blau syndrome. Although most patients described to date depict an otherwise classic Blau syndrome phenotype, the current case was atypical in that the predominant features were arteritic. A novel substitution, G464W, in a highly conserved position near the nucleotide oligomerization domain of the NOD2 protein is also described. Blau syndrome is a monogenic granulomatous disease characterized in its most typical form by a triad of exuberant polyarthritis, uveitis, and granulomatous dermatitis 1 . It is caused by single amino acid substitutions at or near the NACHT domain of NOD2 2 . Although its systemic expression is well recognized after the descriptions of the expanded phenotype of Blau syndrome 3,4 , large-vessel vasculitis remains one of its serious and yet underrecognized manifestations if not actively sought by the treating physician. We describe an 8-year-old girl with symptomatic Takayasu-like arteritis and cardiomyopathy against the background of Blau syndrome with a G464W substitution in NOD2. We reported a similar case in 1989 5 , while others have observed arteritis among children with both sporadic and familial Blau phenotype before the mutation was known MATERIALS AND METHODS A girl, now 11 years old, from rural India, presented to us for the first time at 18 months of age, with bilateral knee effusions of a few months' duration in the absence of rash, uveitis, or systemic features. From the age of 1 month she had had recurrent and unexplained episodes of fever. Her antinuclear antibody result was negative. With a working diagnosis of oligoarticular juvenile arthritis she was administered intraarticular steroids, to which she responded well. She was lost to followup for almost 6 years thereafter. At the age of 8 years, she presented with gradually progressive dyspnea and palpitations of 3 months' duration. She had not thrived, and at this stage she weighed 17.2 kg and her height was 113 cm. There were no systemic features but joint examination showed "boggy synovitis" of the right elbow and knee. Cardiovascular examination showed an irregular pulse with a pulsatile precordium and evidence of congestive heart failure. A rhythm strip on electrocardiography showed ventricular extra beats. The echocardiogram revealed dilated ventricles, generalized hypokinesia with an ejection fraction of 20%, mild tricuspid and aortic regurgitation, and abnormal echogenicity within the wall of the left ventricle. With oligoarticular arthritis in a setting of dilated cardiomyopathy, elevated erythrocyte sedimentation rate, and family history of recurrent unexplained fevers in her mother, a diagnosis of early-onset sarcoidosis was considered. Her eye examination continued to be normal and all biopsies requiring sedation were deferred because of poor cardiac function. Oral methotrexate 10 mg/m 2 and corticosteroids 2 mg/kg were initiated in addition to decongestive treatment consisting of digitalis, diuretics, and captopril. She showed a gradual but steady improvement in effort tolerance, although her ejection fraction on electrocardiography did not mirror her clinical improvement. One and a half years later on a routine followup she was found to be hypertensive. Her carotid pulsations were decreased and a renal bruit was detected. Antihypertensive treatment was instituted and a compute

Therapeutic approaches in the treatment of juvenile dermatomyositis in patients with recent-onset disease and in those experiencing disease flare: An international multicenter PRINTO study

Objective To evaluate response to therapy over a 24-month period in a large prospective international cohort of patients with juvenile dermatomyositis (DM). Methods The study included 145 patients with recent-onset juvenile DM and 130 juvenile DM patients experiencing disease flare, all of whom were \u3c18 years old. Disease activity parameters and therapeutic approaches in 4 geographic areas were analyzed at baseline and at 6, 12, and 24 months. Response was assessed according to the Pediatric Rheumatology International Trials Organization (PRINTO) juvenile DM response criteria, and data were reported as observed and in the intent-to-treat (ITT) population. Results Patients with recent-onset juvenile DM at baseline had higher baseline disease activity and greater improvement over 24 months when compared to juvenile DM patients experiencing disease flare at baseline. Methotrexate (MTX) or high-dose corticosteroids were administered more frequently to patients with recent-onset juvenile DM, compared to juvenile DM patients experiencing disease flare, who were more likely to receive cyclosporine. Compared to patients from Western and Eastern Europe, a higher proportion of patients from South and Central America and North America received pulse steroids, and the average steroid dosage was higher in the North American and South and Central American patients. The use of MTX was similar in all 4 regions, while cyclosporin A was more frequently used in Western Europe. In the as observed analysis, 57.9% of the patients with recent-onset juvenile DM and 36.4% of the patients experiencing disease flare (P \u3c 0.001) reached at least a 70% response by PRINTO criteria at 6 months; these proportions had increased at month 24 to 78.4% and 51.2%, respectively (P \u3c 0.001). Corresponding results of the ITT analysis were much lower, with only one-third of the patients able to maintain the initial assigned therapy over 24 months. Conclusion Patients with recent-onset juvenile DM are more likely to achieve significant clinical improvement over 24 months, when compared to patients experiencing flares of juvenile DM. Internationally, various therapeutic approaches are used to treat this disease. Copyright © 2011 by the American College of Rheumatology

2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative

Objective To develop criteria for the classification of macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (JIA). Methods A multistep process, based on a combination of expert consensus and analysis of real patient data, was conducted. A panel of 28 experts was first asked to classify 428 patient profiles as having or not having MAS, based on clinical and laboratory features at the time of disease onset. The 428 profiles comprised 161 patients with systemic JIA-associated MAS and 267 patients with a condition that could potentially be confused with MAS (active systemic JIA without evidence of MAS, or systemic infection). Next, the ability of candidate criteria to classify individual patients as having MAS or not having MAS was assessed by evaluating the agreement between the classification yielded using the criteria and the consensus classification of the experts. The final criteria were selected in a consensus conference. Results Experts achieved consensus on the classification of 391 of the 428 patient profiles (91.4%). A total of 982 candidate criteria were tested statistically. The 37 best-performing criteria and 8 criteria obtained from the literature were evaluated at the consensus conference. During the conference, 82% consensus among experts was reached on the final MAS classification criteria. In validation analyses, these criteria had a sensitivity of 0.73 and a specificity of 0.99. Agreement between the classification (MAS or not MAS) obtained using the criteria and the original diagnosis made by the treating physician was high (κ = 0.76). Conclusion We have developed a set of classification criteria for MAS complicating systemic JIA and provided preliminary evidence of its validity. Use of these criteria will potentially improve understanding of MAS in systemic JIA and enhance efforts to discover effective therapies, by ensuring appropriate patient enrollment in studies

Expert consensus on dynamics of laboratory tests for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis

Objective: To identify which laboratory tests that change over time are most valuable for the timely diagnosis of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA). Methods: A multistep process, based on a combination of expert consensus and analysis of real patient data, was conducted. A panel of experts was first asked to evaluate 115 profiles of patients with MAS, which included the values of laboratory tests at the pre-MAS visit and at MAS onset, and the change in values between the two time points. The experts were asked to choose the 5 laboratory tests in which change was most important for the diagnosis of MAS and to rank the 5 selected tests in order of importance. The relevance of change in laboratory parameters was further discussed and ranked by the same experts at a consensus conference. Results: Platelet count was the most frequently selected test, followed by ferritin level, aspartate aminotransferase (AST), white cell count, neutrophil count, and fibrinogen and erythrocyte sedimentation rate. Ferritin was most frequently assigned the highest score. At the end of the process, platelet count, ferritin level and AST were the laboratory tests in which the experts found change over time to be most important. Conclusions: We identified the laboratory tests in which change over time is most valuable for the early diagnosis of MAS in sJIA. The dynamics of laboratory values during the course of MAS should be further scrutinised in a prospective study in order to establish the optimal cut-off values for their variation

Evaluation and Management of Deficiency of Adenosine Deaminase 2: An International Consensus Statement

IMPORTANCE: Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited disease characterized by systemic vasculitis, early-onset stroke, bone marrow failure, and/or immunodeficiency affecting both children and adults. DADA2 is among the more common monogenic autoinflammatory diseases, with an estimate of more than 35 000 cases worldwide, but currently, there are no guidelines for diagnostic evaluation or management. OBJECTIVE: To review the available evidence and develop multidisciplinary consensus statements for the evaluation and management of DADA2. EVIDENCE REVIEW: The DADA2 Consensus Committee developed research questions based on data collected from the International Meetings on DADA2 organized by the DADA2 Foundation in 2016, 2018, and 2020. A comprehensive literature review was performed for articles published prior to 2022. Thirty-two consensus statements were generated using a modified Delphi process, and evidence was graded using the Oxford Center for Evidence-Based Medicine Levels of Evidence. FINDINGS: The DADA2 Consensus Committee, comprising 3 patient representatives and 35 international experts from 18 countries, developed consensus statements for (1) diagnostic testing, (2) screening, (3) clinical and laboratory evaluation, and (4) management of DADA2 based on disease phenotype. Additional consensus statements related to the evaluation and treatment of individuals with DADA2 who are presymptomatic and carriers were generated. Areas with insufficient evidence were identified, and questions for future research were outlined. CONCLUSIONS AND RELEVANCE: DADA2 is a potentially fatal disease that requires early diagnosis and treatment. By summarizing key evidence and expert opinions, these consensus statements provide a framework to facilitate diagnostic evaluation and management of DADA2

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

DIFFUSE JUVENILE SYSTEMIC SCLEROSIS PATIENTS SHOW DISTINCT ORGAN INVOLVEMENT, ANTIBODY PATTERN AND HAVE SIGNIFICANTLY MORE SEVERE DISEASE IN THE LARGEST JSSC COHORT OF THE WORLD. RESULTS FROM THE JUVENILE SCLERODERMA INCEPTION COHORT

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