Musculoskeletal measurement tools from the International Prophylaxis Study Group (IPSG<scp>)</scp>

Haemophilia is a sex-linked inherited disorder caused by deficiencies of coagulation factor VIII (haemophilia A) or IX (haemophilia B) [1]. The disorder occurs in all ethnic groups with an estimated frequency of 1 per 5–10 000 live male births. The ratio of haemophilia A to B cases is approximately 4:1. Traditionally, the haemophilias are classified as severe, moderate or mild based on circulating factor levels <1%, 1–5% and >5%, respectively. In many European centres a factor level of <2% is used to define the severe phenotype. The hallmark of the severe haemophilias is recurrent bleeding into joints, in particular, the elbows, knees and ankles, from an early age in life. If these bleeds (haemarthroses) are untreated or inadequately treated, joint damage occurs leading to crippling arthropathy by the second decade of life [2]. Prevention of haemophilic arthropathy is possible by the regular replacement of the deficient clotting factor started at an early age in life, and before any significant joint disease has occurred (primary prophylaxis); if prophylaxis is started at an older age after joint disease has already occurred (secondary prophylaxis), the benefits are significantly diminished [3–5]. The current challenge regarding factor prophylaxis in the haemophilia population relates to affordability as clotting factor concentrates are extremely expensive. Efficacy is not an issue; the results of long-term observational studies plus the recent report of a prospective randomized controlled trial of primary prophylaxis versus on-demand therapy for young boys with severe haemophilia A provide solid evidence in support of regular replacement therapy (prophylaxis) with the aim of preventing recurrent joint bleeding [6–12]. The excellent musculoskeletal results observed in compliant patients on primary prophylaxis regimens has led the World Health Organization (WHO), the World Federation of Hemophilia (WFH) and a number of national haemophilia organizations to recommend primary prophylaxis as a standard of care for young boys with severe haemophilia. The challenge, unfortunately, is cost. Full-dose prophylaxis, defined as the infusion of 20–40 Units of factor VIII given on alternate days or factor IX given twice weekly is extremely expensive. As an example, in Canada in 2001, prophylaxis accounted for 50% of the annual factor VIII use in the country [13]. For the majority of individuals with haemophilia worldwide, the high cost of prophylaxis makes this highly effective management approach a distant dream. In every sense, haemophilia is an example of the clash that results from the wonders of modern day scientific discovery and the reality of delivering affordable, effective healthcare. Thanks to genetic engineering, ultra safe, highly effective recombinant factor VIII and IX clotting factor concentrates are now available for use in the haemophilia population; however, the high cost of these concentrates is the greatest single barrier to the implementation of factor prophylaxis worldwide. It was against this background that, in 2001, the International Prophylaxis Study Group (IPSG) was formed. The International Prophylaxis Study Group (IPSG) is a not-for-profit study group whose mandate is the acquisition of new knowledge concerning factor prophylaxis in persons with inherited bleeding disorders, and the dissemination of this knowledge globally. The coordinating site for the IPSG is The Hospital for Sick Children, Toronto, Canada, and the activities of the study group are overseen by an international steering committee comprised of leaders in the field of haemophilia (see Appendix 1). Funding for activities of the IPSG is provided by unrestricted grants from industry partners to The Hospital for Sick Children Foundation. The key initial focus of the IPSG has been the study of outcome measures other than factor levels, in particular measures related to the early detection and quantification of joint disease using physical examination and imaging techniques such as magnetic resonance imaging (MRI), health-related quality of life (HRQL) measures and economic analyses. The steering committee reasoned that these measurement tools were essential to critically assess different prophylaxis regimens using currently available factor concentrates or, in the future, novel concentrates (e.g. long acting factor VIII/IX preparations). It is hoped that this information generated by the IPSG will help to persuade governments to fund programs of prophylaxis in countries where such treatment is either not available, or available only to individuals/families able to afford the high cost of prophylaxis. The remarkable achievements of two IPSG Working Groups, the Expert Physical Therapy (PT) Working Group and the Expert Imaging Working Group, are the subject of this report. The Expert PT Working Group has developed and tested a new scoring system, the hemophilia joint health score (HJHS) that builds on the orthopaedic joint score recommended by the Orthopedic Advisory Committee of the World Federation of Hemophilia. The new score is optimized for use in young boys with no or minimal joint disease. In parallel, the Expert Imaging Working Group has developed a single international MRI scoring system for use in persons with haemophilia, which can be used to detect and assess minimal and mild structural joint changes that are difficult to evaluate with X-ray. The memberships of these expert working groups (Appendix 1) were drawn from those haemophilia treatment centres active in the field of joint assessment, and includes leading experts in haemophilia care, PT (the Expert PT Working Group) and imaging (the Expert Imaging Working Group). The work performed by these two expert groups to create and test these single international scoring systems is a tribute to international scientific collaboration, and is detailed in the report that follows. A consistent method of measurement and classification of joint health status in individuals with haemophilia is critical for assessing progression of joint disease, establishing or changing treatment protocols and measuring efficacy of treatment regimens or surgical interventions. To address this need, in the early 1980s a group of orthopaedists from Germany, Israel, the UK, Venezuela and the USA developed a measurement and classification instrument known as the World Federation of Hemophilia (WFH) physical examination scale [14]. Although appropriate for measuring the more severe degree of haemophilic joint degeneration (arthropathy) prevalent at the time, psychometric properties of the scale were never established. With the current emphasis on prophylaxis and aggressive infusion protocols the WFH Scale was found to be insensitive to identifying the earliest signs of joint disease. To address this concern, in 1993 the Mountain States Regional Hemophilia Center in Denver, USA modified the WFH scale and began using it in follow-up assessments of radiosynoviorthesis procedures [15]. Several subsequent modifications were made to this scale including changes to facilitate the assessment of young children [16]. This paediatric version was used in the Joint Outcome Study and later in the escalating dose Canadian Hemophilia Primary Prophylaxis Study [17]. Normal values and inter-rater reliability were established. In the late 1990s, the haemophilia centre at the Karolinska Institute in Stockholm, Sweden made further revisions to the tool [18]. These two centres met in 2002 and identified and agreed upon the need for a common assessment tool that could be used internationally to classify joint health status. At the invitation of the International Prophylaxis Study Group (IPSG), these centres along with representatives from Montreal and Toronto, Canada and Utrecht, The Netherlands met to form the Expert PT Working Group. The task of the working group was to consolidate the two scales into one scoring instrument that would be sensitive to early joint change, account for normal development in children and be reliable, valid and practical to administer. The goal of the group was to propose and test a measure of joint structure/function that could replace the World Federation of Hemophilia Orthopedic Scale [14]; it was felt that the WFH scale was insensitive to mild changes seen in children treated with prophylaxis and it inappropriately scored normal developmental changes in children as being pathologic. The PT group currently has representation from Europe (Pia Petrini, Britt-Marie Bergstrom, Marijke van den Berg, JanJaap van der Net) and North America (Marilyn Manco-Johnson, Sharon Funk, Pamela Hilliard, Nick Zourikian, Brian Feldman). This instrument is known as the HJHS. The first developmental meeting of the HJHS occurred in Montreal, Canada in 2003. At that meeting, the Stockholm and Denver scales were presented by their developers [19]. The scales were contrasted and compared. Like items were retained in the HJHS – unique items were discussed and included if there was consensus by the group. A great deal of discussion around the scoring of items (remembering the purpose of the new scale) was initiated at the Montreal meeting, and continued by the group over the next several months. The included items examined for each child are: Swelling, Duration (swelling), Muscle Atrophy, Axial Alignment, Crepitus on motion, Flexion Loss, Extension Loss, Instability, Joint Pain, Strength and Gait. Each item is scored for six index joints (both elbows, knees and ankles) except for axial alignment and gait that are not scored for the elbows. Each item is scored in categories of severity. The total possible score for all six joints is 144; normal joints will score 0. The current version of the scale is included as Appendix 2. As a first step, a reliability study was performed in Toronto, Canada; the HJHS proved to have very high intra- and inter-rater reliability [20]. Subsequent to further minor modifications in the scale, a guidance document and supporting DVD were produced – the purpose being to allow non-IPSG evaluators to reliably use the HJHS. The HJHS was then studied in five centres (Stockholm, Utrecht, Montreal, Denver and Toronto) to confirm its construct validity and to compare its measurement properties with the WFH orthopaedic joint score. The HJHS has excellent construct validity; however, certain items in the scale have been identified as poorly sensitive, or poorly discriminatory. The current scale correlates well with joint specific and overall global physician assessments of joint health. It differentiates children on prophylaxis from those being treated on-demand. It can differentiate children with severe haemophilia from those with milder disease, even in centres that exclusively treat with prophylaxis. Completion of the validity study of the HJHS has provided insight into further modifications that need to be made to the tool. These include the removal of redundant or rarely endorsed items that may not predict or discriminate early signs of joint change. A second version of the HJHS should include testing with different patient populations as well as utilization of the tool by therapists who were not involved in its design. Long-term follow-up studies on the original participants in the validation study and on a cohort of age-matched non-haemophilia subjects are also being considered. The HJHS is available for use both in clinical and research models. The committee has requested submission of proposals defining specifically how the tool is to be used, as it is still being studied and refined. Use of the HJHS will be monitored and the committee requests that feedback be given on how the instrument performs to further identify problems and clarify unclear items. The initial presentation of the HJHS to the haemophilia community worldwide is scheduled for the World Federation of Hemophilia Congress in Istanbul, Turkey in June, 2008. It is anticipated that there will be additional training sessions scheduled in the future. Assessment of joint changes in patients with haemophilia by the use of conventional radiography (X-ray) has been a helpful tool for the evaluation of haemophilic arthropathy for several decades. Today, improvements in haemophilia care and increased acceptance of prophylaxis make the use of more sensitive imaging strategies necessary. MRI is more sensitive than X-ray for early and subtle soft tissue changes after haemarthrosis and is thus well suited for evaluation of prophylaxis. An international consensus MRI scale is important for comparison of data from clinical trials. MRI has the advantage of detecting the earliest and even subclinical manifestations of arthropathy. However, compared with an X-ray scoring method, a joint scoring method based on MRI has considerable extra challenges. MRI is a more complicated, expensive, and time-consuming technique. Imaging evaluation may require the investigation of up to six index joints (elbows, ankles and knees), which is very demanding especially for young patients who may require sedation. MR imaging detail depends on the imaging time, hence, a protocol for evaluating multiple joints results in less detailed images for each individual joint. Also, X-ray reflects primarily bone changes and more severe cartilage destruction that tends to be irreversible, while MRI detects all components of arthropathy – including soft tissue changes that may both progress and regress; MRI is a less uniform imaging technique than X-ray is, and an MRI score reflects a more dynamic process than an X-ray score does. For these reasons the development of a single standardized MRI method for haemophilic arthropathy is a difficult task. Between 2000 and 2004, six alternative MRI scoring methods for haemophilic arthropathy were described in the literature [21–25]. All systems apply one of two basic computing strategies; they are either progressive (the most advanced change determines the score) or additive (the sum of changes determines the score). The two different strategies mimic the Arnold Hilgartner X-ray scale [26] and Pettersson X-ray score [27], respectively. The six original MRI scoring systems also differ with regards to exactly what pathological components they include, their exact definitions, as well as the level of detail of the assessments. If several different MRI scoring methods are adopted, comparison of results will be hampered. For this reason, the Expert Imaging Group of the IPSG worked from 2002 to 2007 to achieve a standardized method (Fig. 1) for MRI assessment of haemophilic arthropathy. An 8-year-old boy with moderate haemophilia A and no previous history of joint bleeds or use of inhibitors. Although both his radiographs and MR images showed evidence of advanced haemophilic arthropathy, MRI was able to demonstrate a larger variety and number of osteochondral changes. The frontal (a) and lateral (d) plain film views of the patient’s left ankle show flattening of the talar dome with narrowing of the tibiotalar joint. Focal zones of erosion are seen extensively in the talus and less extensively in the distal tibial epiphysis. The fibular epiphysis appears enlarged. The radiographs were scored as grade 8 according to the Pettersson scale and as 4 according to the Arnold–Hilgartner scale. Corresponding un-enhanced coronal T1-weighted spin-echo (SE)(b) and multiplanar gradient-recalled (MPGR) (c), sagittal T1-weighted SE (e), and inversion-recovery (f) images of the left ankle are shown. They reveal irregularity of the articular surface of the talar dome (>1/3 of the surface), subchondral cystic defects within the lateral aspect of the distal tibial epiphysis surrounded by bone marrow oedema and joint space narrowing. The MR images received a score of 10 as per the P scale and a score of 16 as per the A scale which constitute the maximum scores for the osteochondral domain of the scales. No associated soft tissue changes were noted. Radiographic scales: Petterson scale -> enlargement of epiphysis (=1), pronounced irregularity of subchondral surface (=2), >50% narrowing of joint space (=2), >1 subchondral cyst (=2), presence of erosions at joint margins (=1). Arnold-Hilgartner scale = narrowing of the joint space and cartilage destruction (=4). Compatible MRI scales: P scale -> maximum changes of subchondral bone or joint margins (=8), maximum cartilage loss (=10). A scale -> maximum changes of subchondral bone or joint margins (=8), maximum cartilage loss (=8). First, the clinimetric properties of the original progressive Denver [28] and additive European [23] MRI scales were investigated for knees and ankles. Four experienced radiologists reviewed 47 MRI examinations performed at three centres on 1.5 Tesla scanners. For all examinations gradient-echo sequences, which enable visualization of the articular cartilage, fluid and haemosiderin deposition, were available. The ability to detect haemosiderin relates to the visualization of susceptibility artefacts caused by extracellular haemosiderin within soft tissues seen especially well on gradient echo images. The results demonstrated that the two MRI scoring systems had comparable inter- and intra-reader reliability [29]. However, it was still not known whether a progressive or additive scoring method was the most expedient, nor what level of detail was feasible and necessary to meet clinical and scientific needs. Thus, to initiate standardization, and to facilitate further evaluation, a single MRI scoring (the MRI was from the original Denver and European MRI scales. the Expert Imaging Group tested the reliability and construct validity of the MRI scale for evaluation of and elbows, and compared the of MRI and plain film radiographs for assessment of these For the investigation of knees and ankles, 1.5 Tesla MR images of knees and ankles – from boys 4 to 16 – were reviewed by radiologists on two The number of previous joint bleeds and of haemophilia were the progressive and the additive components of the scale demonstrated high inter- and intra-reader With to the the MRI scale osteochondral domain and age was moderate additive and progressive and clinical were With to validity of the MRI and scales and no were the – for late changes. The MRI scales performed for of early joint however, at a level for for the additive = and for the progressive = With to the assessment of elbows, MR examinations of from haemophilic boys were reviewed by experienced In this the reliability of MRI scores was – for the additive and excellent for the progressive the intra-reader reliability was excellent for both progressive and additive The MRI scores to with clinical and of however, a number of subjects with severe haemophilia had been on long-term prophylaxis, to the moderate haemophilic phenotype. In that the MRI scales were highly reliable, may not be as at detecting especially at the elbows. based on by the use of this scoring as well as other previous MRI scales a single 16 additive MRI scale for haemophilic arthropathy was In this optimized MRI scale, soft tissue changes were given more with the aim of the detection of early soft tissue changes. Also, the number of items in the osteochondral domain was in the score for soft tissue changes and for osteochondral changes are The use of one single MRI scale will facilitate international comparison of A report of the Expert Imaging Working Group including the new optimized scale and on for imaging protocols for MRI assessment of haemophilic arthropathy will be for The IPSG Expert PT and Imaging Working have developed and tested new tools for the evaluation of musculoskeletal changes in children with haemophilia. These new tools are especially suited for use in young boys with severe haemophilia who are on programs of primary prophylaxis. They will as important outcome measures in prospective studies of both primary and prophylaxis. They will also have a in the assessment and follow-up of patients who procedures such as of the Expert PT and Imaging Working of the IPSG will be to and evaluate practical protocols for clinical use of these new and to compare MRI with for assessment of musculoskeletal disease in persons with haemophilia. of the International Prophylaxis Study Group are by unrestricted grants from and that is the Hospital for Sick Children Toronto, would also to the Hemophilia for their support of the Hemophilia Joint Health validation IPSG Brian Marijke van den Physical Therapy Expert Working Manco-Johnson, Petrini, Britt-Marie Bergstrom, Brian Sharon Funk, Pamela Hilliard, van der Marijke van den Berg, Zourikian, Imaging Expert Working

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