We have previously shown that a single portal vein infusion of a recombinant adeno-associated viral vector (rAAV) expressing canine Factor IX (F.IX) resulted in long-term expression of therapeutic levels of F.IX in dogs with severe hemophilia B. We carried out a phase 1/2 dose-escalation clinical study to extend this approach to humans with severe hemophilia B. rAAV-2 vector expressing human F.IX was infused through the hepatic artery into seven subjects. The data show that: (i) vector infusion at doses up to 2 x 10(12) vg/kg was not associated with acute or long-lasting toxicity; (ii) therapeutic levels of F.IX were achieved at the highest dose tested; (iii) duration of expression at therapeutic levels was limited to a period of approximately 8 weeks; (iv) a gradual decline in F.IX was accompanied by a transient asymptomatic elevation of liver transaminases that resolved without treatment. Further studies suggested that destruction of transduced hepatocytes by cell-mediated immunity targeting antigens of the AAV capsid caused both the decline in F.IX and the transient transaminitis. We conclude that rAAV-2 vectors can transduce human hepatocytes in vivo to result in therapeutically relevant levels of F.IX, but that future studies in humans may require immunomodulation to achieve long-term expression.

Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response

Hemophilia is a rare disorder that is complex to diagnose and to manage. These evidence-based guidelines offer practical recommendations on the diagnosis and general management of hemophilia, as well as the management of complications including musculoskeletal issues, inhibitors, and transfusion-transmitted infections. By compiling these guidelines, the World Federation of Hemophilia aims to assist healthcare providers seeking to initiate and/or maintain hemophilia care programs, encourage practice harmonization around the world and, where recommendations lack adequate evidence, stimulate appropriate studies.

/pdf/guidelines-for-the-management-of-hemophilia-1x6t2d999b.pdf

Guidelines for the management of hemophilia.

Sixty-five boys younger than 30 months of age were randomly assigned to prophylaxis (32 boys) or enhanced episodic therapy (33 boys). When the boys reached 6 years of age, 93% of those in the prophylaxis group and 55% of those in the episodic-therapy group were considered to have normal index-joint structure on MRI (P = 0.006). The relative risk of MRI-detected joint damage with episodic therapy as compared with prophylaxis was 6.1 (95% confidence interval, 1.5 to 24.4). The mean annual numbers of joint and total hemorrhages were higher at study exit in the episodic-therapy group than in the prophylaxis group (P<0.001 for both comparisons). High titers of inhibitors of factor VIII developed in two boys who received prophylaxis; three boys in the episodic-therapy group had a life-threatening hemorrhage. Hospitalizations and infections associated with central-catheter placement did not differ significantly between the two groups. Conclusions Prophylaxis with recombinant factor VIII can prevent joint damage and decrease the frequency of joint and other hemorrhages in young boys with severe hemophilia A. (ClinicalTrials.gov number, NCT00207597.)

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Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia.

Pre-clinical studies in mice and haemophilic dogs have shown that introduction of an adeno-associated viral (AAV) vector encoding blood coagulation factor IX (FIX) into skeletal muscle results in sustained expression of F.IX at levels sufficient to correct the haemophilic phenotype. On the basis of these data and additional pre-clinical studies demonstrating an absence of vector-related toxicity, we initiated a clinical study of intramuscular injection of an AAV vector expressing human F.IX in adults with severe haemophilia B. The study has a dose-escalation design, and all patients have now been enrolled in the initial dose cohort (2 x 10(11) vg/kg). Assessment in the first three patients of safety and gene transfer and expression show no evidence of germline transmission of vector sequences or formation of inhibitory antibodies against F.IX. We found that the vector sequences are present in muscle by PCR and Southern-blot analyses of muscle biopsies and we demonstrated expression of F.IX by immunohistochemistry. We observed modest changes in clinical endpoints including circulating levels of F.IX and frequency of FIX protein infusion. The evidence of gene expression at low doses of vector suggests that dose calculations based on animal data may have overestimated the amount of vector required to achieve therapeutic levels in humans, and that the approach offers the possibility of converting severe haemophilia B to a milder form of the disease.

Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector

The orientation of an acetabulum or an acetabular prosthesis may be described by its inclination and anteversion. Orientation can be assessed anatomically, radiographically, and by direct observation at operation. The angles of inclination and anteversion determined by these three methods differ because they have different spatial arrangements. There are therefore three distinct definitions of inclination and anteversion. This paper analyses the differences between the definitions and provides nomograms to convert from one to another. It is recommended that the operative definitions be used to describe the orientation of prostheses and that the anatomical definitions be used for dysplastic acetabula.

The definition and measurement of acetabular orientation.

In Sweden, prophylactic treatment of boys with severe haemophilia has been practised since 1958 in an attempt to convert the disease from a severe to a milder form. The present study population consisted of 60 severe haemophiliacs (52 A, 8 B), aged 3-32 years. Treatment is started when the boys are 1-2 years of age, the regimens used being 24-40 IU F VIII kg-1 three times weekly in haemophilia-A cases (i.e. greater than 2000 IU kg-1 annually) and 25-40 IU F IX kg-1 twice weekly in haemophilia-B cases. The orthopaedic and radiological joint scores (maximum scores of 90 and 78, respectively) are evaluated as recommended by the World Federation of Haemophilia. Of those subjects aged 3-17 years, 29 out of 35 individuals had joint scores of zero. The oldest group had only minor joint defects. The VIII:C and IX:C concentrations had usually not fallen below 1% of normal. All 60 patients are able to lead normal lives. In conclusion, it appears to be possible to prevent haemophilic arthropathy by giving effective continuous prophylaxis from an early age, and preventing the VIII:C or IX:C concentration from falling below 1% of normal.

Twenty-five years' experience of prophylactic treatment in severe haemophilia A and B

A new, exclusively radiologic classification of hemophilic arthropathy is based on a review of 54 patients who had had repeated radiologic examinations of all great joints before the institution of any specific treatment. In terms of a score, the severity of the arthropathy may be assessed in a single joint, in a single patient, or in a group of patients. Using the score system, the natural course of hemophilic arthropathy demonstrated that the severity of the arthropathy increased with age and degree of coagulation defect. All patients over 5 years of age with severe hemophilia were affected and the radiologic changes were progressive. There was a good correlation between the radiologically assessed severity of the arthropathy and the clinical findings.

A radiologic classification of hemophilic arthropathy.

Objectives. To review long-term prophylactic factor treatment in young patients with severe haemophilia A and B, focusing on the orthopaedic and radiological outcome.

Design. We received 34 patients with severe haemophilia A (n=29) and B (n=5), aged 7–22 years. Age at start of treatment was 1–4.5 years. Dosages of factor concentrate (F VIII and F IX, respectively) were 25–40 IU/kg body weight, three times a week for haemophilia A and twice a week for haemophilia B. The patients had been checked annually over a 5-year period (1990–95). Orthopaedic and radiological joint scores were evaluated according to recommendations by the World Federation of Haemophilia.

Setting. All results were obtained at the Department for Coagulation Disorders, University of Lund, Malmo University Hospital, Malmo, Sweden.

Results. Orthopaedic and radiological joint scores were found to have remained unchanged during follow-up in almost all patients and to be still zero (i.e. no unaffected joints) in 79% (n=27) of the patients.

Conclusion. There is a growing international consensus haemophilic arthropathy can be prevented by administering early high-dose prophylaxis. The results of the present investigation strongly support this opinion.

Haemophilia prophylaxis in young patients–a long‐term follow‐up

Six patients, with giant cell tumors of bone treated by curettage and bone cementing, were followed radiographically for 4 (2–6) years postoperativelyThe radiolucent zones between cortical bone and cement increased in width up to 05 mm during the first 6 months and then remained stationary During the same period the zone adjacent to cancellous bone increased up to 25 mm and was surrounded by a sclerotic rim In two cases the zone adjacent to cancellous bone diminished by 1–15 mm during the first 2 years after surgery There was a positive correlation between the maximal width of the zone adjacent to cancellous bone and the volume of cement fillingsOur findings indicate that the radiolucent zone surrounding bone cement is caused by thermal necrosis

https://www.tandfonline.com/doi/pdf/10.3109/17453678408992403

Bone cement, thermal injury and the radiolucent zone

A new method of measuring vertical dislocation of the C1 and C2 vertebra in rheumatoid arthritis is presented based on the distance from the lower end plate of C2 to the palato -occipital or McGregor 's line. In a normal material the distance was found to be 34 mm or more in men and 29 mm or more in women. A value below these limits should be regarded as vertical dislocation. In the same normal material the value according to the McGregor method was found to be 9 mm or less in both sexes. In a combined material consisting of healthy individuals and patients with rheumatoid arthritis a good correlation between the two measurement methods was found. The new method has the advantage of giving a measurable value also in cases with advanced dislocations and an undiscernible dens and of giving a correct value in cases with erosions and destruction of the dens.

Holger Pettersson

Papers

Twenty-five years' experience of prophylactic treatment in severe haemophilia A and B

A radiologic classification of hemophilic arthropathy.

Haemophilia prophylaxis in young patients–a long‐term follow‐up

Bone cement, thermal injury and the radiolucent zone

Radiographic Measurements of the Cranio-Vertebral Region: Designed for Evaluation of Abnormalities in Rheumatoid Arthritis