Study Identifies Cytokine Target for Treatment-Resistant Hemophilia A

Bhavya Doshi, MD

Findings from a new study shed light on the mechanisms behind patient unresponsiveness to coagulation protein therapy for hemophilia A.

More specifically, investigators note a key target that may lead to treatment failure in up to 30% of patients.

Currently, hemophilia is the most common inherited bleeding disorder, which affects 1 in 10,000 men across the globe. Since patients lack coagulation factor VIII (FVIII), therapies are typically aimed at infusions to replace the missing protein.

Some patients, however, become treatment resistant due to the development of neutralizing antibodies, or FVIII inhibitors.

Nonetheless, an investigation into the immune response mechanism, led by Bhavya Doshi, MD, and colleagues at the Children’s Hospital of Philadelphia (CHOP), examined the regulatory role of cytokine B cell activating factor (BAFF) towards FVIII inhibitors.

The Context

Previous research has shown that BAFF has some role in certain autoimmune diseases, as well as in antibody-mediated transplant rejections.

“Recent studies in allograft transplant recipients demonstrate that high BAFF levels prior to transplant are associated with antibody-mediated rejection and elevated levels following α-CD20 therapy may also contribute to the failure to induce humoral tolerance to the graft,” the investigators wrote.

In addition to BAFF, a proliferation-inducing ligand (APRIL) expression is notably increased under proinflammatory responses.

Despite these observations, however, the investigators note that the mechanisms behind FVIII inhibitor development have been very much unclear.

The Findings

The investigators used plasma samples from 69 pediatric patients undergoing recombinant FVIII therapy, in addition to samples from mouse models, to determine whether BAFF may help generate and sustain FVIII antibodies.

Of the pediatric patients, 24 had FVIII inhibitors.

From their analysis, they found BAFF levels to be higher in patients with persistent FVIII inhibitors compared to those without inhibitors (1.30 vs. 0.99 ng/mL, respectively, P = 0.021).

“Moreover, BAFF levels decreased from baseline in hemophilia A inhibitor patients who underwent ITI [immune tolerance induction] and achieved FVIII tolerance from 1.43 ± 0.63 to 0.81 ± 0.32 ng/mL (P = 0.025),” the investigators observed. “In comparison, those who failed ITI had steady levels at 1.33 to 1.23 ng/mL (P = 0.246.).

A similar pattern and trend in BAFF levels was also noted for an adult population (n = 46), although noninhibitor patients saw a generally higher level of BAFF.

Furthermore, a receiver-operating characteristic (ROC) analysis of the pooled pediatric and adult data showed that BAFF levels greater than 1.03 ng/mL had 68.3% sensitivity, 63.8% specificity, and likelihood ratio of 1.89 for the presence of FVIII inhibitors.

The mouse models revealed that using prophylactic anti-BAFF therapy prior to FVIII treatment successfully prevented inhibitors. As for the mice with already-developed inhibitors, treatment with anti-BAFF and rituximab had an effect of reducing FVIII inhibitor titers.

“Our data suggest that BAFF may regulate the generation and maintenance of FVIII inhibitors, as well as anti-FVIII B cells," said co-investigator Valder R. Arruda, MD, PhD, director of CHOP's NIH-funded Center for the Investigation of Factor VIII Immunogenicity, in a statement.

“Given that an FDA-approved anti-BAFF antibody is currently used to suppress the immune response in autoimmune diseases, future research should explore the use of this treatment in combination with rituximab to achieve better outcomes for hemophilia A patients resistant to FVIII protein replacement therapy,” he indicated.

The study, “B cell–activating factor modulates the factor VIII immune response in hemophilia A,” was published online in The Journal of Clinical Investigation.