Optimal treatment strategies for hemophilia: achievements and limitations of current prophylactic regimens.

Evaluation of prophylactic treatment of haemophilia requires sensitive methods. To design and test a new magnetic resonance imaging (MRI) scale for haemophilic arthropathy, two scales of a combined MRI scoring scheme were merged into a single scale which includes soft tissue and osteochondral subscores. Sixty-one joint MRI's of 46 patients with haemophilia were evaluated by four radiologists using the new and older scales. Forty-six of the joints were evaluated using two X-ray scales. For all MRI scores, interreader agreement and correlations with X-ray scores and lifetime number of haemarthroses were analysed. The interreader agreement intraclass correlation coefficient was 0.82, 0.89 and 0.88 for the soft tissue and osteochondral subscores and the total score, as evaluated according to the new MRI scale, compared to 0.80 and 0.89 as for the older scales. The total score and osteochondral subscore according to the new scale, as well as scores according to the older scales were correlated (P 0.05) was found between the soft tissue subscore of the new MRI scale and the X-ray scores. The new MRI scale is simpler to apply than the older and has similar reader reliability and correlation with lifetime number of haemarthroses, and by separating soft tissue and osteochondral changes it gives additional information. The new scale is useful for analyses of early and moderate stages of arthropathy, and may help to evaluate prophylactic haemophilia treatment.

An MRI scale for assessment of haemophilic arthropathy from the International Prophylaxis Study Group.

Outcome assessment in haemophilia is important to assess results of prophylactic treatment. Recently, the Haemophilia Joint Health Score (HJHS) was developed to assess early joint damage in children with haemophilia. Thus, the aim of this study was to assess reliability and explore validity of the HJHS in teenagers and young adults with haemophilia. Twenty-two patients with haemophilia (mean age 20.4, range 14-30, including 15 severe) were assessed by the HJHS1.0, Haemophilia Activities List (HAL), SF36 and self-evaluation was performed using a Visual Analogue Scale (VAS) scale. A subset of 12 patients were assessed by three physiotherapists to establish interobserver reliability (intraclass correlation coefficient: ICC). Total HJHS1.0 scores were calculated without overall global gait. Validity was explored by the assessment of Pearson's correlation with all outcome parameters and recent Pettersson scores. Overall outcome was good, with median HJHS score of 5.5 of a maximum 144 (range 0-34), median patients' VAS of 96.5 and maximum scores for HAL and SF36 physical functioning for the majority of patients. Pettersson scores were low (median 3.5 of 78, N = 18). Interobserver reliability was good (ICC 0.84), with limits of agreement of ±7.2 points. ICC was unaffected by different score calculation methods. Exploration of validity in 22 patients showed weak correlations of HJHS scores with patients' VAS (0.33) and HAL (-0.40) and strong correlations with SF36-PF (-0.66) and Pettersson scores (0.86). These results suggest that interobserver reliability of the HJHS1.0 in teenagers and young adults with limited joint damage is excellent. Preliminary data on validity were similar or better than those in children.

Using the Haemophilia Joint Health Score for assessment of teenagers and young adults: exploring reliability and validity.

Introduction
The implementation of early long-term, regular clotting factor concentrate (CFC) replacement therapy (‘prophylaxis’) has made it possible to offer boys with haemophilia a near normal life. Many different regimens have reported favourable results, but the optimum treatment regimens have not been established and the cost of prophylaxis is very high. Both for optimizing treatment and reimbursement issues, there is a need to provide objective evidence of both short- and long-term results and benefits of prophylactic regimens.

Aims
This report presents a critical review of outcome measures for use in the assessment of musculoskeletal health in persons with haemophilia according to the International Classification of Functioning, Disability and Health (ICF). This framework considers structural and functional changes, activities and participation in a context of both personal and environmental factors.

Methods
Results were generated by a combination of a critical review of available literature plus expert opinion derived from a two day consensus conference between 48 health care experts from different disciplines involved in haemophilia assessment and care. Outcome tools used in haemophilia were reviewed for reliability and validity in different patient groups and for resources required.

Results and conclusion
Recommendations for choice of outcome tools were made according to the ICF domains, economic setting, and reason for use (clinical or research). The next step will be to identify a ‘core’ set of outcome measures for use in clinical care or studies evaluating treatment.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/hae.13088

Choosing outcome assessment tools in haemophilia care and research: a multidisciplinary perspective.

In patients with haemophilia A, factor VIII (FVIII) prophylaxis reduces bleeding frequency and joint damage compared with on-demand therapy. To assess the effect of prophylaxis initiation age, magnetic resonance imaging (MRI) was used to evaluate bone and cartilage damage in patients with severe haemophilia A. In this cross-sectional, multinational investigation, patients aged 12–35 years were assigned to 1 of 5 groups: primary prophylaxis started at age <2 years (group 1); secondary prophylaxis started at age 2 to <6 years (group 2), 6 to <12 years (group 3), or 12−18 years (group 4); or on-demand treatment (group 5). Joint status at ankles and knees was assessed using Compatible Additive MRI scoring (maximum and mean ankle; maximum and mean of all 4 joints) and Gilbert scores in the per-protocol population (n = 118). All prophylaxis groups had better MRI joint scores than the on-demand group. MRI scores generally increased with current patient age and later start of prophylaxis. Ankles were the most affected joints. In group 1 patients currently aged 27−35 years, the median of maximum ankle scores was 0.0; corresponding values in groups 4 and 5 were 17.0 and 18.0, respectively [medians of mean index joint scores: 0.0 (group 1), 8.1 (group 2) and 13.8 (group 4)]. Gilbert scores revealed outcomes less pronounced than MRI scores. MRI scores identified pathologic joint status with high sensitivity. Prophylaxis groups had lower annualized joint bleeds and MRI scores vs. the on-demand group. Primary prophylaxis demonstrated protective effects against joint deterioration compared with secondary prophylaxis.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/hae.12539

Controlled, cross-sectional MRI evaluation of joint status in severe haemophilia A patients treated with prophylaxis vs. on demand

The clinical relevance of subtle changes on magnetic resonance imaging (MRI) for evaluating haemophilia treatment is unknown. To determine the relationship of findings on MRI with joint function and bleeding in joints with apparently very mild arthropathy, a prospective study was performed. Knees and ankles of 26 patients, 13-26 years, were scanned. Two blinded radiologists scored the MRI (IPSG consensus score) and the radiography [Pettersson score (PS)]. Clinical function (HJHS) was scored by one physiotherapist. Life-time number of bleeds was collected from patient files. Of 104 joints scanned, three were excluded because of previous arthrodesis or trauma. Remaining 101 MRI scores correlated weakly with clinical function (r = 0.27, P = 0.01) and less with lifetime number of bleeds (r = 0.16, P = 0.14). MRI scores were 0 in 58 joints, including 27 with major bleeds. In three joints of patients playing intensive sports MRI showed minor changes (MRI score = 1) in the absence of bleeds. Agreement was reasonable between PS and MRI score (r = 0.41, P < 0.01). In 30% of joints, MRI detected abnormalities in soft-tissue and cartilage, while PS was 0 points. No evidence of occult haemorrhages was found. Instead, we found no abnormalities on MRI in 43 joints with a history of repeated joint bleeding. Haemosiderin seemed associated with the time between assessment and last bleed; joints that had suffered a bleed long before MRI had hardly haemosiderin, while those with a recent bleed showed haemosiderin, suggesting joint damage may be reversible. Abnormalities detected by MRI, but not by PS were minor and their clinical implications are not yet clear.

A. M. A. De Schepper

Papers

Magnetic resonance imaging in teenagers and young adults with limited haemophilic arthropathy: baseline results from a prospective study.