Current Controversies in the Formation and Treatment of Alloantibodies to Factor VIII in Congenital Hemophilia A

Kruse‐Jarres, Rebecca

doi:10.1182/asheducation-2011.1.407

Cited by 20 publications

(22 citation statements)

References 32 publications

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“…38,43 The presence of different human FVIII variants in pdFVIII might reduce the likelihood of a formation of high anti-FVIII titers simply due to "antigenic competition". 44,45 In fact, it is widely accepted that fluctuations in the abundance of antigenic variants effectively reduces the immunodominance of a particular variant. …”

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confidence: 99%

Alloantibodies to therapeutic factor VIII in hemophilia A: the role of von Willebrand factor in regulating factor VIII immunogenicity

Oldenburg¹,

Lacroix‐Desmazes

Lillicrap

2015

Haematologica

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The rising incidence of neutralizing antibodies (inhibitors) against therapeutic factor VIII prompted the conduct of studies to answer the question as to whether this rise is related to the introduction of recombinant factor VIII products. The present article summarizes current opinions and results of non-clinical and clinical studies on the immunogenic potential of recombinant compared to plasma-derived factor VIII concentrates. Numerous studies provided circumstantial evidence that von Willebrand factor, the natural chaperone protein present in plasma-derived factor VIII products, plays an important role in protecting exogenous factor VIII from uptake by antigen presenting cells and from recognition by immune effectors. However, the definite contribution of von Willebrand factor in reducing the inhibitor risk and in the achievement of immune tolerance is still under debate. ABSTRACTinhibitors in stable PTPs after switching treatment is consistently lower than in previously untreated patients (PUPs), 31,32 probably because many of them have developed some kind of cross-tolerance. Thus, the immunogenicity of a given FVIII concentrate in PTPs is relevant for PTPs only. However, in daily clinical practice, more situations that demand a decision between treatment options are related to PUPs, i.e. patients in their early years of life who are newly diagnosed with hemophilia A or who sustain their first bleeding episode. 27,33 Are inhibitor testing methods a critical confounder?One of the most cited arguments used to confute a higher incidence of inhibitors associated with rFVIII treatment is that the testing frequencies and methods used for the detection of inhibitors have increased and improved over time. These improvements coincide with the introduction of rFVIII, which might have favored the detection of borderline and transient inhibitors in rFVIII-treated patient groups. 23,31,34 In fact, in 1995, the so-called "Nijmegen" method, a modification of the till then most widely used "Bethesda assay", was launched. 35 However, despite the improvements made over recent years, the methods used to detect inhibitors have not yet been standardized, 28,36 and the classical Bethesda assay originally published in 1975 is still the most frequently used assay. 34,36 Furthermore, the major advantage of the Nijmegen modification of the Bethesda assay lies in the improvement in the test's specificity near the cut-off value. 28,35,37 Hence, the advent and use of the Nijmegen assay should have caused a decrease in the rate of false positive test results and, consequently, a decrease rather than an increase in the inhibitor incidence in studies dating back to the 1990s. On the other hand, it is very possible that the increased testing frequency in the last two decades had an impact on the reported incidence of inhibitors. Studies reporting on the incidence of high-responding inhibitors [> 5 Bethesda units (BU) per milliliter] (Figure 1) avoided potential bias from assay performance and testing frequencies, because high-res...

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confidence: 99%

Alloantibodies to therapeutic factor VIII in hemophilia A: the role of von Willebrand factor in regulating factor VIII immunogenicity

Oldenburg¹,

Lacroix‐Desmazes

Lillicrap

2015

Haematologica

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“…Management of inhibitor consists of immune tolerance therapy and application of activated prothrombin complex concentrate or recombinant factor VIIa [26]. We have to take into account that although prophylactic treatment in the early age is worthwhile, it can make the patient susceptible to inhibitor formation and make the management more difficult [25].…”

Section: Discussionmentioning

confidence: 99%

“…So, we decided to divide it into three divisions. We divided the sum scores into weak (FISH score 8-16), moderate (FISH score 17-24) and good (FISH score [25][26][27][28][29][30][31][32]. For evaluating the level of functional deficit in a 2 9 2 table, we categorized the weak and moderate levels into Disordered Group and the good level into Not-Disordered Group.…”

Section: Scoringmentioning

confidence: 99%

Influencing factors on the functional level of haemophilic patients assessed byFISH

Kachooei

Badiei²,

Zandinezhad³

et al. 2013

Haemophilia

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Joint destruction in early adulthood brings the patients to the orthopaedic clinics. If a haemophilic patient becomes disabled, it shows a number of factors such as timely diagnosis, availability of appropriate treatment depending on the country, access and affordability to treatments and equally importantly the responsibility of the patient in managing self care by remaining compliant by prescribed treatment regimen. We assessed the functional level by functional independence score in haemophilia (FISH). Overall, 104 patients with haemophilia A and 29 with haemophilia B were evaluated. We assessed the function of the patients by FISH. We divided the sum scores into weak (FISH score 8-16), moderate (17-24), and good (25-32). For evaluating the level of functional deficit in a 2 × 2 table, we categorized the weak and moderate levels into Disordered Group and the good level into Not-Disordered Group. The average age was 26.9 ± 14.24. Each 1 year increase in age can increase 1.07 fold the possibility of being placed in Disordered Function Group. Severe haemophilia can increase 7.34 fold, presence of inhibitor can increase 9.75 fold and home self-care increases 3.89 fold the possibility of being placed in Disordered Function Group. To decrease the burden of the cost on patient, family and the government, education plays the most important role. We suggest that we send a trained team of physician and nurses to the deprived villages and cities instead of waiting for the patient to refer to our Care Center.

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“…The highest risk for the formation of inhibitors is observed in patients with mutations (46). Factors that may increase the risk of inhibitor development include younger age at first treatment and high treatment intensity and dose (47). Certain haemophilic mutations are also associated with an increased risk of inhibitor development.…”

Section: Haemophiliamentioning

confidence: 95%

Practical guidance on immunogenicity to biologic agents used in the treatment of psoriasis: What can be learnt from other diseases?

Lambert

Nast

Nestle

et al. 2015

Journal of Dermatological Treatment

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The clinical efficacy of biologic agents for the treatment of moderate to severe psoriasis is well proven in clinical studies, but patients may lose response over time. Loss of response may be due to immunogenicity and the formation of anti-drug antibodies (ADA). Although data on the immunogenicity of drugs used to treat psoriasis are now emerging, more information on the impact of factors, such as dosing regimens and concomitant immunosuppressive therapy is needed. Exploring research from other disease areas where immunogenicity has long been recognised as a significant clinical issue may help in developing future strategies for using drug level and ADA measurements to help tailor biologic therapy to meet individual needs. To this end, we analyse what is known about biologics and immunogenicity in psoriasis. In order to learn from other indications, we then address the issue of immunogenicity for three different types of biologic treatments. First, factor VIII-substitution in haemophilia, where the immune system is newly exposed to a physiologic but formerly absent protein. Second, the use of biologics in inflammatory bowel disease, where similar treatment challenges apply as observed in psoriasis. Third, immunogenicity in multiple sclerosis caused by therapeutic antibodies or interferons. Immunogenicity strategies used in other disease areas will need to be tested in psoriasis before they can be widely adopted in routine clinical practice.

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Current Controversies in the Formation and Treatment of Alloantibodies to Factor VIII in Congenital Hemophilia A

Cited by 20 publications

References 32 publications

Alloantibodies to therapeutic factor VIII in hemophilia A: the role of von Willebrand factor in regulating factor VIII immunogenicity

Alloantibodies to therapeutic factor VIII in hemophilia A: the role of von Willebrand factor in regulating factor VIII immunogenicity

Influencing factors on the functional level of haemophilic patients assessed byFISH

Practical guidance on immunogenicity to biologic agents used in the treatment of psoriasis: What can be learnt from other diseases?

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