Comparing the burden of illness of haemophilia between resource-constrained and unconstrained countries: the São Paulo-Toronto Hemophilia Study.

INTRODUCTION: Although the regular replacement of clotting factor concentrates (prophylaxis) has been well established as the standard of care for severe haemophilia, the high cost of factor concentrates has limited access to prophylaxis in countries with under-developed or developing economies. AIMS: We studied the health gap that could be addressed by providing unlimited access to clotting factor concentrates with implementation of long-term prophylaxis initiated from an early age in life. METHODS: We performed a cross-sectional study of a random, representative sample of boys with moderate and severe haemophilia at three haemophilia treatment centres in Sao Paulo, Brazil, and one centre in Toronto, Canada. RESULTS: Canadian subjects were more often treated with prophylaxis, and began treatment at an earlier age. Fewer Canadian subjects had bleeds within the preceding 6 months (19 vs. 34, P = 0.003). Canadian subjects had lower (better) Pettersson radiographic scores (1.5 vs. 6.0, P = 0.0016), lower (better) Hemophilia Joint Health Scores (5.5 vs. 10.5, P = 0.0038), higher (better) Activity Scale for Kids scores (96.6 vs. 92.0, P = 0.033), more time spent in vigorous activity, and higher (better) social participation scores. CONCLUSIONS: Our findings suggest that increasing access to clotting factor concentrates for young boys with severe haemophilia is a global imperative.

Development of CAPTSureTM - a new index for the assessment of pediatric postthrombotic syndrome.

Essentials We developed a discriminative and evaluative index for pediatric postthrombotic syndrome (PTS). A Delphi-survey was used for item reduction and multi-criteria decision analysis for item weighting. The new index assesses limb PTS based on the relative severity of each sign and symptom. Higher scores related to higher odds of parental dissatisfaction with their child's condition. SUMMARY: Background Postthrombotic syndrome (PTS) is a complication of deep vein thrombosis defined by the presence of characteristic signs and symptoms. We developed a discriminative and evaluative index for the assessment of upper extremity (UE) and lower extremity (LE) pediatric PTS. Methods The items to be included in the index were voted for by 26 pediatric thrombosis experts invited to participate in a Delphi survey. Subsequent item weighting was based on item importance elicited by the use of multicriteria decision analysis (MCDA); 122 healthcare providers and patients/parents were invited to participate in item weighting. The implications of the overall scores were explored by comparison with PTS diagnosis (independently assessed by two clinical experts) and parental satisfaction/dissatisfaction with their child's current condition. Results Items voted for inclusion by at least 70% of the Delphi survey respondents (81% response rate) were pain, paresthesia, swelling, heaviness, endurance, collateral circulation and arm circumference difference for the UE, and pain, paresthesia, swelling, heaviness, tightness, tired limb, redness/purple or blotchy skin, endurance, ulcers and thigh/calf circumference difference for the LE. Items were then weighted by the use of MCDA (82% response rate). The index had excellent discrimination for patients with/without PTS. For every 10-point increase in index scores (with higher scores being indicative of worse PTS), the odds of parental dissatisfaction increased by 75% and 92% in the UE and LE, respectively. Conclusion We report the development of the CAPTSure™ (index for the Clinical Assessment of Postthrombotic Syndrome in children), which reflects collective judgement of the severity of pediatric PTS. We also provide information on the meaning of the scores.

Correlating clinical and radiological assessment of joints in haemophilia: results of a cross sectional study.

OBJECTIVES: This study was undertaken to determine the correlation between the radiological changes in haemophilic arthropathy [X-ray, Ultrasound (US) and MRI] and clinical assessment as determined by the Hemophilia Joint Health Score (HJHS); and to document the US and MRI changes in joints that appear normal on plain X-ray and clinical evaluation. MATERIALS AND METHODS: Of 55 study joints (22 knees and 33 ankles) in 51 patients with haemophilia/von Willebrand disease, with a median age of 15 years (range: 5-17) were assessed using X-rays (Pettersson score) and clinical examination (HJHS) at two centres (Toronto, Canada; Vellore, India). MRI and ultrasonographic scoring was done through a consensus assessment by imagers at both centres using the IPSG MRI and US scores. RESULTS: The HJHS had a good correlation with the Pettersson score (rs = 0.66). Though the HJHS had moderate correlation with the osteochondral component of the MRI and US scores (rs 0.51, 0.45 respectively), its correlation with the soft tissue component was poor (rs 0.19; 0.26 respectively). Of the 18 joints with a Pettersson score of zero, 88.9% had changes that were detected clinically by the HJHS. Osteochondral abnormalities were identified in 38.9% of these joints by the MRI, while US images of the same joints were deemed abnormal in 83.3% by the current criteria. US identified haemosiderin and other soft tissue changes in all of the joints, while the same changes were noted in 94.4% of these joints on MRI. There were four joints with a HJHS of zero, all of which had soft tissue changes on MRI (score 1-7) and US (score 2-7). Osteochondral changes were detected in three of these joints by US and in 2 by MRI. There were four joints with an MRI score of 0-1 that had significant US scores (3-5) and HJHS scores (0-6). CONCLUSION: US and MRI are able to identify pathological changes in joints with normal X-ray imaging and clinical examination. However, further studies are required to be able to differentiate early abnormalities from normal. Clinical (HJHS) and radiological assessment (US/MRI) provide complimentary information and should be considered conjointly in the assessment of early joint arthropathy.

Haemophilia prophylaxis: how can we justify the costs?

Severe haemophilia results in increased mortality and poorer quality of life. Factor prophylaxis leads to a more normal life, but is very costly; most of the cost is due to the high cost of replacement factor. Despite its high cost, factor prophylaxis has been adopted throughout the developed world--even in different health care systems. We argue that there are at least five possible reasons why societies may value factor prophylaxis despite its cost: (i) it is directed towards an inherited disease, (ii) the treatment is largely directed towards children, (iii) the disease is rare and the overall cost to society is small, (iv) the treatment is preventative, and v) the high cost is largely the result of providing safe products. In an era of rising health care costs, there is a strong research agenda to establish the factors that determine the value of expensive therapies for rare diseases like haemophilia.

Validation of the Actiheart activity monitor for measurement of activity energy expenditure in children and adolescents with chronic disease.

BACKGROUND/OBJECTIVES: The purpose of this study was to develop an activity energy expenditure (AEE) prediction equation for the Actiheart activity monitor for use in children with chronic disease. SUBJECTS/METHODS: In total, 63 children, aged 8-18 years with different types of chronic disease (juvenile arthritis, hemophilia, dermatomyositis, neuromuscular disease, cystic fibrosis or congenital heart disease) participated in an activity testing session, which consisted of a resting protocol, working on the computer, sweeping, hallway walking, steps and treadmill walking at three different speeds. During all activities, actual AEE was measured with indirect calorimetry and the participants wore an Actiheart on the chest. Resting EE and resting heart rate were measured during the resting protocol and heart rate above sleep (HRaS) was calculated. RESULTS: Mixed linear modeling produced the following prediction equation: This equation results in a nonsignificant mean difference of 2.1 J/kg/min (limits of agreement: -144.2 to 148.4 J/kg/min) for the prediction of AEE from the Actiheart compared with actual AEE. CONCLUSIONS: The Actiheart is valid for the use of AEE determination when using the new prediction equation for groups of children with chronic disease. However, the prediction error limits the use of the equation in individual subjects.

Cost-utility analysis of Canadian tailored prophylaxis, primary prophylaxis and on-demand therapy in young children with severe haemophilia A.

Primary prophylaxis is the emerging standard treatment for boys with severe haemophilia. Tailored (escalating-dose) prophylaxis (EscDose), beginning at a low frequency and escalating with repeated bleeding may prevent arthropathy at a lower cost than standard prophylaxis (SP). From a societal perspective, we compared the incremental cost per joint-haemorrhage that is avoided and quality-adjusted-life-year (QALY) gained of SP and EscDose to on-demand (Demand) therapy in severe haemophilia A boys treated to age 6 using a decision analytic model. Costs included factor VIII (FVIII), professional visits and tests, central venous placement/complications, hospitalization, home programmes and parents' lost work-days. Resource utilization was estimated by surveying 17 Canadian clinics. The natural history of bleeding and other probabilities were determined from a longitudinal chart review (n = 24) and published literature. EscDose costs an additional $3192 per joint-haemorrhage that was avoided compared with Demand whereas SP costs an additional $9046 per joint-haemorrhage that was avoided compared with EscDose. Clinic costs and lost wages were reduced by 60-80% for EscDose and SP compared with Demand. EscDose attained more QALYs than SP and Demand on account of less bleeding than Demand and lower need for ports than SP. The incremental cost per QALY for EscDose vs. Demand was $542 938. EscDose was less expensive with similar QALYs compared to SP. Sensitivity analysis was performed on all probability- and cost-estimates, and showed the model was sensitive to the cost of FVIII and the SP and target joint utilities. In conclusion, prophylaxis will substantially improve clinical outcomes and quality of life compared to Demand treatment, but with substantial cost.

Assessment of an infectious disease history preceding juvenile dermatomyositis symptom onset.

OBJECTIVES: A number of studies have looked at the role of infectious diseases in triggering juvenile dermatomyositis (JDM). Previous studies have found a moderately high frequency of infectious symptoms prior to disease onset; however, no specific pathogens could be identified. We sought to correlate preceding infectious symptoms with onset and outcomes of JDM. METHODS: We studied an inception cohort of all JDM cases diagnosed at The Hospital for Sick Children (SickKids) between 1988 and 2006. Data pertaining to symptoms at onset, diagnosis and disease outcomes were abstracted. Two independent paediatric infectious disease specialists reviewed all records of patients with symptoms or tests suggestive of infection. RESULTS: A total of 110 patients were reviewed; of these, 78 had sufficient information about disease onset for inclusion. Potential indications of an infectious process prior to JDM onset were found in 55/78 (71%) patients and were further evaluated for evidence of infection temporally associated with symptom onset. Features suggestive of infection prior to JDM symptom onset were found in 40/55 [probable (30/40) or possible (10/40)]. Most children with probable infections had respiratory illnesses [24/30 (80%)]. Fewer patients than expected had disease onset during summer months. The presence of an infection at onset was not found to be associated with differences in characteristics at diagnosis or disease outcomes. CONCLUSIONS: A substantial number of JDM patients have a clinical history consistent with an infection prior to onset. Newly diagnosed patients should undergo a full infectious disease assessment as part of their initial work-up; specific attention should be given to respiratory infections.

Recommendations for reporting economic evaluations of haemophilia prophylaxis: a nominal groups consensus statement on behalf of the Economics Expert Working Group of The International Prophylaxis Study Group.

BACKGROUND: The need for clearly reported studies evaluating the cost of prophylaxis and its overall outcomes has been recommended from previous literature. OBJECTIVES: To establish minimal ''core standards'' that can be followed when conducting and reporting economic evaluations of hemophilia prophylaxis. METHODS: Ten members of the IPSG Economic Analysis Working Group participated in a consensus process using the Nominal Groups Technique (NGT). The following topics relating to the economic analysis of prophylaxis studies were addressed; Whose perspective should be taken? Which is the best methodological approach? Is micro- or macro-costing the best costing strategy? What information must be presented about costs and outcomes in order to facilitate local and international interpretation? RESULTS: The group suggests studies on the economic impact of prophylaxis should be viewed from a societal perspective and be reported using a Cost Utility Analysis (CUA) (with consideration of also reporting Cost Benefit Analysis [CBA]). All costs that exceed $500 should be used to measure the costs of prophylaxis (macro strategy) including items such as clotting factor costs, hospitalizations, surgical procedures, productivity loss and number of days lost from school or work. Generic and disease specific quality of lífe and utility measures should be used to report the outcomes of the study. CONCLUSIONS: The IPSG has suggested minimal core standards to be applied to the reporting of economic evaluations of hemophilia prophylaxis. Standardized reporting will facilitate the comparison of studies and will allow for more rational policy decisions and treatment choices.

The Cutaneous Assessment Tool: development and reliability in juvenile idiopathic inflammatory myopathy.

OBJECTIVES: Clinical care and therapeutic trials in idiopathic inflammatory myopathies (IIM) require accurate and consistent assessment of cutaneous involvement. The Cutaneous Assessment Tool (CAT) was designed to measure skin activity and damage in IIM. We describe the development and inter-rater reliability of the CAT, and the frequency of lesions endorsed in a large population of juvenile IIM patients. METHODS: The CAT includes 10 activity, 4 damage and 7 combined lesions. Thirty-two photographic slides depicting IIM skin lesions were assessed by 11 raters. One hundred and twenty-three children were assessed by 11 paediatric rheumatologists at 10 centres. Inter-rater reliability was assessed using simple agreements and intra-class correlation coefficients (ICC). RESULTS: Simple agreements in recognizing lesions as present or absent were generally high (0.5-1.0). ICCs for CAT lesions were moderate (0.4-0.75) in both slides and real patients. ICCs for the CAT activity and damage scores were 0.71 and 0.81, respectively. CAT activity scores ranged from 0 to 44 (median 7, potential range 0-96) and CAT damage scores ranged from 0 to 13 (median 1, potential range 0-22). The most common cutaneous lesions endorsed were periungual capillary loop changes (63%), Gottron's papules/sign (53%), heliotrope rash (49%) and malar/facial erythema (49%). CONCLUSIONS: Total CAT activity and damage scores have moderate to good reliability. Assessors generally agree on the presence of a variety of cutaneous lesions. The CAT is a promising, semi-quantitative tool to comprehensively assess skin disease activity and damage in IIM.

Recent developments in clinimetric instruments.

Assessment of impairment and function is essential in order to monitor joint status and evaluate therapeutic interventions in patients with haemophilia. The improvements in the treatment of haemophilia have required the development of more sensitive tools to detect the more minor dysfunctions that may now be apparent. This paper outlines some of the recent developments in this field. The Haemophilia Joint Health Score (HJHS) provides a systematic and robust measure of joint impairment. The MRI Scoring System has been designed to provide a comprehensive scoring system combining both progressive and additive scales. The Functional Independence Score for Haemophilia (FISH) has been developed to assess performance of functional activities and can be used in conjunction with the Haemophilia Activities List (HAL) which provides a self report measure of function. It is recommended that both measures are evaluated as these tools measure different constructs. Further refinement and testing of the psychometric properties of all of these tools is in progress. More widespread use of these tools will enable the sharing of data across the world so promoting best practice and ultimately enhancing patient care.

Cost of severe haemophilia in Toronto.

Our objective was to determine costs and trends in treating boys with severe haemophilia A before our centre routinely used prophylaxis. One reviewer extracted data from patient charts to determine resource consumption for 17 boys with severe haemophilia A from 1978 to 1998 at Toronto's Hospital for Sick Children. Resources included factor concentrate, doctors and health care professionals (physiotherapists/social workers), tests (laboratory, radiological and diagnostic) and hospitalizations. Subgroup analysis on those patients infected with HIV and/or hepatitis were also performed. Costs in Canadian Dollars were taken from standard lists and discounted at 3%. Total average cost (range) 62 292 dollars (3339-121 738) per year patient(-1); the largest fraction, 59 910 dollars (3103-119 480), 96.2% was accounted for by factor VIII. Hospitalizations accounted for 1832 dollars (0-5217) per patient year(-1) including drugs, nursing care and stay. Doctor and health care professionals visits averaged 252 dollars (36-462) and 72 dollars (0-175) per patient year(-1), laboratory and other tests cost 201 dollars (22-377) and 26 dollars (2-60) per patient year(-1), respectively. The average number of bleeds was 12.9 (2.0-22.0) per patient year(-1), decreasing since 1977 by 0.68 per patient year(-1) (R(2) = 0.56). Hospitalizations averaged 0.22 (0-4) per patient year(-1), lasting 2.3 days. From 1984, hospitalizations decreased by 0.025 patient(-1) year(-1) (R(2) = 0.76). Concurrently, the average treatment costs increased by 5456 dollars patient(-1) year(-1) (R(2) = 0.81). Clotting factor concentrate cost per patient increased by 5521 dollars year(-1) (R(2) = 0.82). Patients with virally transmitted diseases had considerable higher costs. The cost per year was substantial. Costs increased with virally transmitted diseases. Number of bleeds and hospitalizations over the period of study decreased and costs increased because of factor use in secondary prophylaxis.

Cost-utility analysis in evaluating prophylaxis in haemophilia.

Prophylaxis is an expensive form of management in haemophilia but has demonstrated many advantages with respect to decreasing joint bleeds and potentially preventing joint damage. The valuation of prophylaxis and how the costs and benefits of this intervention compare with other interventions in the management of haemophiliacs can be evaluated through cost-utility analysis (CUA). CUA is an economic method of analysis where the benefits of a healthcare intervention are expressed as an overall utility or preference, usually in the form of quality-adjusted life years (QALYs). This is a composite measure, which takes into consideration both an individual's lifespan and quality of life (QoL). The most difficult aspect of performing a CUA is the measurement of health-related QoL (HRQoL). Much work is ongoing into evaluating HRQoL in haemophiliacs. This paper addresses some of the ways in which this can be achieved and some of the problems with evaluating HRQoL. Ultimately CUA may provide a tool to allow societies to decide if prophylaxis is worth the cost and how the costs and benefits of prophylaxis compare to other healthcare interventions for other disease entities.

Health-related quality-of-life treatments for severe haemophilia: utility measurements using the Standard Gamble technique.

Prophylaxis for haemophilia improves outcomes, but at a substantial cost. Cost-utility analysis balances improvements seen in health-related quality of life (HRQoL) against costs, with the purpose of aiding healthcare decision-making. This analysis uses a measure of HRQoL known as utility. The objective of this study was to measure HRQoL (utility) values for states of health that result from on-demand therapy or prophylaxis. The HRQoL for different health states (including target joint bleeding, different intensities of prophylaxis, and indwelling intravenous catheters [ports]) was measured for healthy adults (n=30), parents of haemophilic children (n=30), and adults with haemophilia (n=28). Parents and patients rated health states similarly. Healthy adults gave the lowest ratings. The following rank, in order of HRQoL, was obtained: prophylaxis (low > medium > high) > on-demand therapy > prophylaxis with port> prophylaxis with infected port > on-demand therapy with development of a target joint. We conclude that: (1) haemophilia and its treatment reduce HRQoL; (2) prophylaxis is preferred to on-demand therapy; (3) intravenous ports substantially reduce HRQoL; (4) and an intravenous port to provide prophylaxis is preferable to on-demand therapy if a target joint develops.

Validation of the Childhood Health Assessment Questionnaire in the juvenile idiopathic myopathies. Juvenile Dermatomyositis Disease Activity Collaborative Study Group.

OBJECTIVE: To examine the validity of the Childhood Health Assessment Questionnaire (CHAQ) in patients with juvenile idiopathic inflammatory myopathy (IIM). METHODS: One hundred fifteen patients were enrolled in a multicenter collaborative study, during which subjects were assessed twice, 7-9 months apart. Physical function was measured using the CHAQ. Internal reliability was assessed using adjusted item-total correlations and item endorsement rates. Construct validity was assessed by comparing predicted and actual correlations of the CHAQ with other measures of physical function and disease activity. Responsiveness was assessed by calculating effect size (ES) and standardized response mean (SRM) in a group of a priori defined "improvers." RESULTS: Item-total correlations were high (rs range = 0.35-0.81), suggesting all items were related to overall physical function. Manual muscle testing and the Childhood Myositis Assessment Scale correlated moderate to strongly with the CHAQ (r = -0.64 and -0.75, both p < 0.001). Moderate correlations were also seen with the physician global assessment of disease activity (rs = 0.58, p < 0.001), parent global assessment of overall health (rs = -0.65, p < 0.001), Steinbrocker function class (rs = 0.69, p < 0.001), and global skin activity (rs = 0.40, p < 0.001), while global disease damage and skin damage had low correlations (rs = 0.13 and 0.07, p > or =0.17). Responsiveness of the CHAQ was high, with ES = 1.05 and SRM = 1.20. CONCLUSION: In this large cohort of patients with juvenile IIM, the CHAQ exhibited internal reliability, construct validity, and strong responsiveness. We conclude that the CHAQ is a valid measure of physical function in juvenile IIM, appropriate for use in therapeutic trials, and potentially in the clinical care of these patients.

Sensitivity of the Systemic Lupus Erythematosus Disease Activity Index, British Isles Lupus Assessment Group Index, and Systemic Lupus Activity Measure in the evaluation of clinical change in childhood-onset systemic lupus erythematosus.

OBJECTIVE: To investigate whether 3 disease activity indices commonly used to evaluate systemic lupus erythematosus (SLE) in adults are sensitive to clinical change in children, and thus suitable for the use in the management of childhood-onset SLE. METHODS: Thirty-five SLE patients who were newly diagnosed between 1993 and 1997, had an age at onset of 6-16 years (26 female and 9 male), and were currently being followed up at The Hospital for Sick Children (followup of 9 months to 4 years) were reviewed. The SLEDAI (Systemic Lupus Erythematosus Disease Activity Index), BILAG (British Isles Lupus Assessment Group index), and SLAM (Systemic Lupus Activity Measure) were applied at up to 4 occasions during the disease course: at the time of diagnosis, 6 months postdiagnosis, at the time of a flare (a deterioration in clinical presentation or laboratory results requiring initiation or increase of either corticosteroids or "second-line" drugs), and 6 months postflare. The sensitivity of the 3 measures to change, as gauged by the effect size (ES), effect size index (ESI), standard response mean (SRM), responsiveness statistic (RS), and relative efficiency index (REI), were compared. RESULTS: All 3 tools were very sensitive to change in disease activity (ES >0.8, ESI >2.3, SRM >0.6, RS >0.86, REI >0.72), but were ranked differently depending on the statistic used for comparison. CONCLUSION: All 3 measures of disease activity are highly sensitive to clinical change in children; none showed an overall superiority. The SLEDAI, BILAG, and SLAM can all be used to study response to treatment in children with SLE.

Assessment of myocardial perfusion and function in childhood systemic lupus erythematosus.

OBJECTIVES: To determine the prevalence of abnormalities in myocardial perfusion or function in children with systemic lupus erythematosus (SLE), and describe potential factors that may predict their development. STUDY DESIGN: Patients (n = 40; 30 female) were enrolled through the Lupus Clinic at The Hospital for Sick Children between 1990 and 1992. Resting and exercise thallium myocardial perfusion scans, radionuclide angiography with multiple gated acquisition (MUGA), and resting M-mode and two-dimensional echocardiography were performed. RESULTS: All patients were free of symptoms, and none had a history of ischemic heart disease. Their median age was 15.9 years (range 10.5 to 19.8 years) at enrollment. Abnormalities of coronary perfusion were found in 5 (16%) of 31 patients (95% confidence interval: 3%, 29%) and included a large fixed perfusion defect in 1; 5 of 27 MUGA scans showed marginally low left ventricular ejection fractions at rest, whereas all had normal exercise responses. In the group with abnormal thallium scans, three of five patients had antiphospholipid antibodies detected, and two of four had an abnormal plasma lipid profile. This group tended to have a shorter disease duration and had received a lower cumulative dose of corticosteroids; these differences were not statistically significant compared with the group with normal scans. CONCLUSION: Asymptomatic abnormalities of myocardial perfusion occur in children with SLE and are more common than previously suspected. Patients with these abnormalities of myocardial perfusion may be predisposed to the previously recognized early-onset ischemic heart disease seen in adults with SLE.

Measuring disability in juvenile dermatomyositis: validity of the childhood health assessment questionnaire.

OBJECTIVE: Physical disability is perhaps the most important outcome of juvenile dermatomyositis (JDM). No functional assessment tool has been validated for inflammatory myopathies either in children or adults. We studied the measurement properties of the Childhood Health Assessment Questionnaire (CHAQ) in children with JDM. METHODS: We studied 37 patients followed at the JDM clinic and compared the results obtained by the CHAQ to a global disease severity score and quantitative muscle strength testing measured by sphygmomanometry (construct validity). We also measured the reliability of the CHAQ and its responsiveness to clinical change. RESULTS: For the initial measurement of each subject, the correlation between disease severity and CHAQ was high [Spearman's correlation, (rs = 0.71, p < 0.002)]. Disability as measured by the CHAQ was inversely correlated with proximal muscle strength (hip abduction rs = -0.57, p < 0.002; shoulder abduction rs = -0.51, p < 0.01) but, as expected, less so with more distal muscle strength (knee extension rs = -0.40, p = 0.05; grip strength rs = -0.079, p > 0.20). The CHAQ was reliable in subjects who showed no clinical change in muscle strength (intraclass correlation coefficient = 0.87) and responsive to treatment induced clinical change (responsiveness coefficient = 0.90). CONCLUSION: The CHAQ can serve as a valid and sensitive tool in the evaluation of functional outcomes in JDM.