Improved joint health shown with intensive FVIII replacement therapy
Patients 5 times more likely to see easing of synovial hypertrophy: Study
Hemophilia patients who received intensive factor VIII (FVIII) replacement therapy for better joint health were nearly five times more likely to see a reduction or complete resolution of synovial hypertrophy — swelling and thickening of the connective tissue that lines the inside of a joint — compared with those treated with standard FVIII replacement therapy.
That’s according to a new study from researchers in Italy, who also found that one-quarter of the patients in the intensive treatment group had complete resolution of synovial hypertrophy — a milestone observed in fewer than 3% of those who received standard treatment.
“To the best of our knowledge, this is the first randomized and controlled study prospectively evaluating the efficacy of intensive replacement treatment … on [synovial hypertrophy] reduction/resolution in [people with hemophilia],” the researchers wrote.
The team added that their results “were entirely confirmed” by an analysis involving 127 patient joints that were identified as having synovial hypertrophy. The study’s findings showed “a consistently higher rate of [synovial hypertrophy] reduction and resolution in elbows, knees and ankles of patients receiving intensive treatment as compared to [those given] standard treatment,” the researchers wrote.
The study, “Intensive FVIII replacement in haemophilia patients with hypertrophic synovium: a randomized study,” was published in the Journal of Thrombosis and Haemostasis.
Targeting the swelling of connective tissue lining the insides of joints
Hemophilia A, the most common form of the disease, occurs when blood fails to clot properly due to the lack or malfunction in the body of a clotting protein called FVIII. As a result of poor clotting, people with hemophilia experience heavy and prolonged bleeding episodes. A hallmark sign of hemophilia, especially in severe cases, is bleeding into the joints.
When bleeding occurs in a joint, inflammation develops in the synovium — the connective tissue inside the joint — causing it to thicken. This process is known as synovial hypertrophy.
It can, in turn, cause damage to bones and cartilage, and such degenerative changes can cause joint disease. Thus, synovial hypertrophy can be an early sign of joint disease and an overall marker of hemophilia disease activity.
The gold standard prophylactic, or preventive, treatment for hemophilia A is FVIII replacement therapy, in which patients receive infusions of the clotting factor they are missing to prevent or reduce the frequency of bleeds. However, some research suggests that patients who are receiving standard prophylactic treatment still experience joint disease.
“Although some recommendations [suggest tailoring] treatment and intensifying factor VIII (FVIII) prophylaxis in the presence of [synovial hypertrophy], literature evidence [is] limited and no studies defining the optimal prophylactic schedule in this clinical setting are available,” the researchers wrote.
Now, a team led by researchers at Federico II University in Naples investigated whether a more intensive regimen of FVIII replacement therapy might be more effective at treating synovial hypertrophy and improving joint health compared with standard FVIII replacement therapy.
Their Phase 4 study (NCT04784988) involved a total of 75 people with hemophilia A. Among them, 39 were given intensive FVIII replacement therapy, with a targeted FVIII activity level of 8% to 12%. The other 36 patients received standard FVIII replacement therapy, with a targeted FVIII activity level of 3% to 5% per current guidelines. The participants’ joint health was evaluated every three months.
In about 50% of cases, study participants experienced synovial hypertrophy in multiple joints.
Three patients in the standard treatment group (8.4%) achieved a reduction or resolution of synovial hypertrophy after a median time of 16 months, with two patients (5.6%) experiencing a reduction and one patient (2.8%) achieving resolution.
In contrast, 14 patients in the intensive treatment group (35.9%) achieved a reduction or resolution of synovial hypertrophy after a median time of 12 months. Four of these patients (10.3%) experienced reduction and 10 (25.6%) achieved complete resolution of synovial hypertrophy.
Better joint health seen in elbows, knees, ankles with intensive treatment
Statistical analyses also revealed that the intensive treatment regimen was associated with a 4.75 times greater likelihood of enabling patients to see a reduction or resolution of synovial hypertrophy compared with standard treatment. The intensive treatment also was associated with a 10.79 times greater chance of providing synovial hypertrophy resolution compared with standard therapy.
The annual bleeding rate, or ABR, was lower in the intensive treatment group than in the standard treatment group (mean of 1.03 vs. 0.49). Additionally, 59% of intensively treated patients had an ABR of zero, meaning they had no bleeding episodes, compared with 36.1% of those in the standard treatment group.
Clinical assessment of joint status for all six major synovial joints — both elbows, knees, and ankles — as measured by the Hemophilia Joint Health Score (HJHS), showed a more significant reduction in the HJHS score after intensive treatment. Indeed, patients in the intensive treatment group saw their HJHS scores drop by 11.9%, while those in the standard treatment group had a reduction of 2.2%.
[Overall,] when compared to standard replacement treatment … we found a [five]fold higher rate of [synovial hypertrophy] reduction/resolution in patients receiving the intensive replacement treatment.
Ultrasound imaging looking for abnormalities in synovial joints similarly found that intensive replacement therapy was more effective at reducing joint damage than standard treatment.
Overall, the team noted that “when compared to standard replacement treatment … we found a [five]fold higher rate of [synovial hypertrophy] reduction/resolution in patients receiving the intensive replacement treatment.”
The researchers hypothesized that even more intensive therapy, with target FVIII levels greater than 8% to 12% could lead to better outcomes, but cautioned that more research was necessary.
“Targeting 30%-40% as FVIII trough levels … [could] induce [synovial hypertrophy] reduction/resolution in a larger percentage of cases, but ad hoc designed studies are needed to confirm this hypothesis,” they wrote.
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