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Abstract

Nowadays, the development of factor VIII and IX inhibitors in patients with hemophilia is considered as the most challenging in the treatment of hemophilia. Immune tolerance induction (ITI) therapy is an approach for eradication of inhibitors. Some ITI protocols are routinely in use for the eradication of inhibitors in patients with hemophilia. Moreover, such a therapeutic regimen may facilitate the tendency to reduced bone density in patients with inhibitor. This study scheduled to investigate whether that predisposing role of ITI protocols with an immunosuppressive agent has considered or not. By a literature review, published ITI protocols in hemophilia with inhibitors were evaluated. Among them, 51 papers found and studied thoroughly. None of them had performed the bone mineral examination in patients with hemophilia and inhibitor under treatment. Since there are 2 coexisting facilitating factors in these protocols, considering the bone mineral density study for patients with inhibitor who are undergoing ITI protocols with an immunosuppressive agent is recommended.

Keywords

hemophilia A hemophilia B immunosuppressive agents immune tolerance induction (ITI)blood coagulation factor inhibitors osteopenia decreased bone mass osteoporosis bone mineral densitometry

Introduction

Hemophilia, the most common bleeding disorder, has a prevalence of around 400 000 individuals worldwide.^1,2 Different genetic abnormalities in factor VIII and IX genes terminate to the absence or reduced plasma levels of factor VIII and IX in the blood.³ These diverse defects translate to various types of bleeding manifestations in the clinical aspect. The standard therapeutic approach is replacement therapy using plasma-derived or recombinant factor VIII and IX concentrate. The main adverse events of replacement therapy include the development of an inhibitor, the risk of thrombosis, and allergic reaction. The development of inhibitors is considered the most challenging topics in hemophilia care in the current decade.⁴ Inhibitors neutralize infused coagulation factor concentrates and makes it an extremely challenging complication in the management of hemorrhagic episodes.⁵ It causes treatment of hemorrhagic episodes in hemophilia more exigent topics and also the economically more expensive treatment for the health providers’ system.^4,6 Improving health and safety surveillance are noticeable topics in a lifelong disease such as hemophilia.⁷ Hence, recognizing, evaluating, and communicating treatment-related adversarial complications are particularly important and should be monitored as early as possible.

Inhibitors in Hemophilia

Development of inhibitors in hemophilia is a multifactorial process that dynamically comprises inherited factors (ABO blood group,⁸ ethnicity,⁹ human leukocyte antigen,¹⁰ haplotype,¹¹ type of factor VIII or factor IX mutations,^12,13 and family history of developing inhibitors¹⁴) and environmental factors (infection and vaccination,^15
–17 type of infused coagulation factor,¹⁸ and age at start of treatment).^8,4,19 About 30% of patients with severe hemophilia A, 0.9% to 7% of patients with moderate and mild hemophilia A,²⁰ and around 3% to 4% of individuals with severe hemophilia B develop inhibitors.^21
–23 The development of inhibitors significantly complicates the control of hemorrhagic episodes in patients with hemophilia and makes challenges for hematologists because bleeds may not respond to conventional replacement therapy.^24,25 Therefore, the development of inhibitors is associated with poor quality of life, higher morbidity rate, and a higher cost of care for health provider systems.²⁶ Patients with a high dose of inhibitors (>5 Bethesda unit) do not respond to standard replacement therapy and need to be managed by a bypassing therapy.²⁷ The current treatment strategy for high-titer inhibitors comprises utilizing a bypassing agent, including activated prothrombin complex concentrates (APCC) FEIBA (Takeda Company) or recombinant activated factor VII (rFVIIa; NovoSeven; Novo Nordisk).^28
–30 In practice, the failure rate of treatment with bypassing agents ranges from 10% to 30%.³¹ Another widely used therapeutic approach is immune tolerance induction (ITI), which leads to an eradication rate of about 70% to 85% of inhibitors.³² Hence, ITI is the first choice option, especially in children with inhibitors.^33
–35 The hallmark protocols for ITI regimens include the Bonn, van Creveld, and Malmö protocols.^36
–38

Susceptibility of Patients With Severe Hemophilia to Reduced Bone Density

Several surveys have demonstrated reduced bone density in patients with severe hemophilia compared to age- and sex-matched control group.^{39

–47} It seems osteopenia and osteoporosis in hemophilia is a multifactorial process. It needs to be cleared pathophysiologically.⁴⁸ Because patients with hemophilia usually experience hemophilia arthropathy secondary to bleeding into joints, they have low physical activity. This phenomenon may cause reduced peak of bone mass during childhood. It can translate to reduced bone density in later stages of life.⁴⁹ The influence of some blood-borne viruses, including hepatitis C virus and HIV, has brought up.⁴⁵ The development of osteoporosis in hemophilia increases the risk of bone fracture during normal daily activities when an occurrence of fracture seems to be an illogical event.⁵⁰ Despite these truths, hemophilia does not considered as a secondary cause of osteoporosis.⁴⁸

Clinical Question

What are the defects of ITI protocol with an immunosuppressive agent that are in employing for the eradication of inhibitors in patients with hemophilia regarding predisposing patients to reduced bone density? How can these defects be improved?

Method

The Strategy of Search

Assessment of the published articles was carried out to unravel whether the facilitator effect of ITI therapies with an immunosuppressive agent to reduced bone density has considered and paid attention or not. Hence, medical search engines of PubMed and Scopus were searched without any time limitation. The literature review was done on English language papers from the past till March 15, 2019. The following keywords were used for searching: “hemophilia A + hemophilia B + immune tolerance induction + ITI + immunosuppressive + inhibitor.” The authors screened the retrieved articles, relevance separately. All types of published articles or e-print of ahead papers, including original article, case series, case report, brief report, and letter to the editor that contains data on patient with hemophilia and inhibitors who underwent ITI protocol, entered to the study. The review articles that discussed ITI protocol and patients with hemophilia and inhibitors were not included in the study. All discrepancies and cross-checking of identifying papers were resolved in a debriefing session. From the target articles, some data were extracted, such as the type of hemophilia, number of treated patients, year of publishing data, type of administrated immunosuppressive agent, the country in which protocol was done, and whether bone density has done or not. And moreover, it was investigated whether the supplementary regimen for protection against reduced bone density has administrated or not?

Results

Overall, 196 related abstracts were identified through the search strategy. After deleting repeated titles, 114 abstracts were selected. Among them, 111 full texts were selected. All 111 full texts read to clear administration of an immunosuppressive agent as part of the ITI protocol and also evaluation of patients for reduced bone density. Among them, 12 review articles and 3 abstracts were excluded from the study. The whole 96 original articles were read. As reflected in the flow diagram of the study, 51 surveys had used at least one of the immunosuppressive agents in their ITI protocols,^{37,51

-99} while 45 studies had used a version of ITI without any immunosuppressive agent (Figure 1). Among the 51 reported studies on the eradication of inhibitors in hemophilia A and B using an immunosuppressive agent or combination of them, the used immunosuppressive agents included mycophenolate mofetil, corticosteroid, rituximab, rapamycin, Solumedrol, dexamethasone, hydrocortisone, prednisolone, prednisone, cyclophosphamide, methylprednisolone, fluprednisolone, and cyclosporine A (Table 1). At the reviewing of articles, about 284 patients with hemophilia A, B, or acquired hemophilia had undergone one of the ITI protocols with at least an immunosuppressive agent in various countries across the world. There was no evidence of the detection status of bone density among studied patients. Moreover, no evidence found about prescription for supplementary calcium for the patients. Among the founded articles in this survey on published articles about the eradication of inhibitors, 29 studies had published between 2000 and 2018 and 22 articles published before 2000. Moreover, Sweden and the United States had reported the most studies (9 articles by each country).

Figure 1.

The inclusion and exclusion flow diagram of studies.

Table 1.

The List of Published Original Articles on Eradication of Factor VIII or IX Inhibitors by ITI Protocols, Including Immunosuppressant Agents Before November 2015.^a

Authors	Year of publication	Hemophilia	Sample size	Country	Immunosuppressant agent	BMD ref.
Freiburghaus et al	1999	A and B	16 and 7	Germany	Cyclophosphamide	³⁸
Yuste et al	2016	A	5	M	NC	⁵¹
Antun et al	2015	A	5	M	NC	⁵²
Kobayashi et al	2015	B	1	Japan	Prednisolone and hydrocortisone	⁵³
Cos and Martorell	2014	A	1	Spain	IV prednisolone	⁵⁴
Batorova et al	2013	B	1	Slovakia	Dexamethasone	⁵⁵
Zhang et al	2010	A	1	China	NC	⁵⁶
Unuvar et al	2008	A	Total 21 treated NC	Turkey	Cyclophosphamide	⁵⁷
Astermark et al	2006	A and B	29 and 5	M	NC	⁵⁸
Nemes and Pitlik	2000	AHA	14	Hungary	Cyclophosphamide and methylprednisolone	⁵⁹
Carlborg et al	2000	A	4	Sweden	Cyclophosphamide	⁶⁰
Nilsson et al	1988	A	11	Sweden	Cyclophosphamide	⁶¹
^bBatlle J et al	1999	A	1/11^c	M	Cyclophosphamide and prednisone	⁶²
Aznar et al	1984	A	5	Spain	Fluprednisolone	⁶³
Kucharski et al	1996	A	15	Poland	Cyclophosphamide	⁶⁴
Nilsson et al	1981	B	1	Sweden	Cyclophosphamide	⁶⁵
Nilsson et al	1995	B	3	Sweden	Cyclophosphamide	⁶⁶
Green et al	1993	AHA	31	United States	Cyclophosphamide and prednisone	⁶⁷
Shibata et al	2003	B	3	Japan	Hydrocortisone	⁶⁸
Pfliegler et al	1989	AHA	1	Hungary	Cyclosporin and Prednisone	⁶⁹
Hedner and Tengborn	1985	A	1	Sweden	Hydrocortisone and cyclophosphamide	⁷⁰
Dormandy and Sultan	1975	A	3	United Kingdom	Cyclophosphamide	⁷¹
Robbins et al	2001	A	2	United States	Dexamethasone and prednisone	⁷²
White et al	2000	A	2	Ireland	Cyclophosphamide and prednisone	⁷³
Gruppo et al	1992	A	8	United States	Cyclophosphamide and prednisone	⁷⁴
Mauser Bunschoten et al	1995	A	2	The=Netherlands	Cyclophosphamide	³⁷
Beutel et al	2009	B	1	Germany	Dexamethasone, MMF, and rituximab	⁷⁵
Thornburg and Ducore	2018	A	1	United States	Solumedrol, rituximab	⁷⁶
Nilsson et al	1976	A and B	9 and 3	Sweden	Cyclophosphamide	⁷⁷
Nilsson et al	1974	A	4	Sweden	Cyclophosphamide	⁷⁸
Ruggeri et al	1975	A	8	Italy and France	Cyclophosphamide	⁷⁹
Kobrinsky et al	2004	A	4	United States	Cyclophosphamide	⁸⁰
Lian et al	1989	AHA and A	12 and 5	United States	Prednisone, vincristine, and cyclophosphamide	⁸¹
Vlot et al	2002	A	1	The Netherlands	Cyclophosphamide	⁸²
Zettervall et al	1985	A	1	Sweden	Cyclophosphamide	⁸³
Nilsson et al	1973	B	1	Sweden	Cyclophosphamide	⁸⁴
Edson et al	1973	A	1	United States	Cyclophosphamide and dexamethasone	⁸⁵
Streif et al	2009	A	2	Germany	Rituximab and cyclosporine A	⁸⁶
Carcao et al	2006	A	5	Canada	Rituximab	⁸⁷
Collins et al	2009	A	15	United Kingdom	Rituximab	⁸⁸
Ranta et al	2011	A	1	Finland	Rituximab	⁸⁹
Barnes et al	2010	B	1	Australia	Rituximab	⁹⁰
Aleem et al	2009	A	3	Saudi Arabia	Rituximab	⁹¹
Chowdhury et al	2006	A	1	United Kingdom	Rituximab	⁹²
Wiestner et al	2002	A	4	United States	Rituximab	⁹³
Dunkley et al	2006	A	3	Australia	Rituximab	⁹⁴
Klarmann et al	2008	B	2	Germany	MMF	⁹⁵
Beck et al	1969	A	2	United Kingdom	Prednisone	⁹⁶
Lin et al	2011	A	1	Taiwan	Prednisone, azathioprine, and methotrexate	⁹⁷
Cross et al	2007	B	1	The Netherlands	Cyclosporin A	⁹⁸
Shaffer et al	1997	AHA	9	United States	Cyclophosphamide and prednisone	⁹⁹

Abbreviations: AHA, acquired hemophilia A; BMD, bone mineral density evaluation; IV, intravenous; M, multicenter; MMF, mycophenolate mofetil; NC, not cited.

^a In the current study, 11 cases have been reported, but only 1 case has received cyclophosphamide and prednisone.

^bThe first author of this manuscript is Batlle J.

^cOne family members exists in this study.

What Does the Reviewing of the Evidence Conclude?

The landscape of the treatment of patients with hemophilia has undergone very speedy and significant advances during recent decades. The various available therapeutic regimens span from plasma-derived coagulation factor concentrate to bypassing agents (rFVII and APCC).^100,101 The coagulation factor concentrates are switching from plasma-derived form to recombinant coagulation factors, and half-life extended coagulation factor.¹⁰² Now bispecific monoclonal antibody that mimics the function of factor VIII (emicizumab) is on trial and usage in developed countries.¹⁰³ There are also multiple therapeutic regimens for eradication of inhibitors too. The ITI protocols consider as the mainstay of eradication of inhibitors in hemophilia.¹⁰⁴ Suppression of T cells, induction of T-cell anergy, inhibition of B cell, and usage of anti-idiopathic antibodies comprise the mechanism action of ITI protocol.¹⁰⁵ Hence, ITI protocols are in use with a 60% to 80% success rate in hemophilia A now.^106,107 On the other hand, there is no therapeutic agent that can provide 100% protection against all hemorrhagic episodes in all patients without concern about the development of inhibitors.

Discussion

Osteoporosis, a disease that involves reduced bone density, results in the impaired and abnormal texture of bone mass that may lead to unforeseen fractures during normal daily activities. Osteoporosis is a significant cause of mortality and morbidity in adults. Indeed, the balance between bone development during childhood and the subsequent bone loss during adulthood comprises the bone mass. The factors, such as smoking, alcoholism, thalassemia, hypogonadism, hematological malignancies, vitamin D deficiency, and some drugs such as exogenous glucocorticoid excess, anticoagulants of warfarin, and heparin, consider to be the secondary predisposing factors toward reduced bone density (RBD). Moreover, the risk of bone fracture correlates with bone architecture in various races, which is evaluated by fracture risk assessment tool (Frax).

Hemophilia presents with a bleeding tendency and reduced plasma levels of coagulation factors VIII and IX in the blood.¹ Some researchers have shown that there is reduced bone density both in the lumbar spine and the femoral bone of males who have hemophilia via several case–control trials.^41,48,108 Osteoporosis in various races’ groups of patients with hemophilia has adequately studied in evidence of the literature. Despite this, hemophilia has not been considered a cause of secondary osteoporosis yet.¹⁰⁹

Apart from this, the development of inhibitors of relevant transfused coagulation factors is a major challenge that complicates the treatments for hemophilia bleeding. There are various types of neutralizing antibodies that bind to relevant coagulation factors and may impair functions of coagulation proteins in the coagulation system. The frequencies of developing inhibitors have generally ranged from approximately 18% to 28% in hemophilia A. The predisposing factors for developing inhibitors determine the severity of hemophilia, the underlying genetic defects, the age of patients at the time of treatment onset, the type of infused coagulation factor concentrates (plasma derived or recombinant factors), and the ethnic background of patients.

Immune tolerance induction is a therapeutic protocol for the eradication of inhibitors in hemophilia. The specific function by which ITI works is not completely clear. Among the suggested targets, it seems that factor VIII-specific T and B cells are more significant.¹¹⁰ The use of ITI therapy may require 12 months of treatment to observe improvements. It may require 2 years or longer period in more complicated patients with hemophilia and inhibitors.^111,112 Some ITI protocols comprise the use of one or more immune suppressant agents (corticosteroids, cyclophosphamide, etc). Additionally, glucocorticoid-induced osteoporosis has addressed entirely in the literature.^113,114 It seems safety, pharmacoeconomic, and efficacy aspects of ITI therapy need to be designated.¹¹⁵ Hence, for patients with hemophilia and inhibitor who tend to have reduced bone density, when they undergo ITI protocol (with at least an immunosuppressive agent) for the eradication of inhibitors, it is expected that they will have a higher risk for reduced bone density.

The limitation of the current study includes restricting the search to English papers. Although English is the universal language for scientific reports of studies, there may be other published papers in this field and this topic in local languages has been missed in our literature review.

Conclusion

Various ITI protocols are in use for the eradication of factor VIII and IX inhibitors in patients with hemophilia A and B. Some of ITI protocols include one or more immunosuppressive agent that has known to be associated with the side effect of reduced bone density. On the other hand, it has demonstrated that patients with hemophilia tend to have reduced bone density secondary to various factors. These 2 ameliorating factors push patients with hemophilia and inhibitors who are receiving ITI protocols with an immunosuppressive agent toward reduced bone density. This gap has not considered in the treatment of the current patients and needs to pay attention as a part of the ITI protocols for the patients with hemophilia and inhibitors. The ultimate goal of this study is to follow patients with hemophilia and inhibitor about bone mineral status before beginning of any ITI protocol with an immunosuppressive agent. Apart from this, in future versions of ITI protocols, evaluation of bone mineral density would be taken account. According to the current literature review, there is a body of evidence that implies bone mineral density in patients with inhibitors has not been considered. It is, thus, clearly accepted that well-planned randomized trials will shed more light on this issue.

Future Prospects

At the moment, the bone mineral examination is not routinely performed for patients with hemophilia. At present, tendency to reduced bone density has demonstrated in patients with hemophilia. And moreover, immunosuppressive agents pave the way toward osteopenia, and it would be expected that bone mineral examination should to be done for them. In addition, for patients with hemophilia and inhibitors who want to eradicate inhibitors by an immunosuppressive agent, a supplementary regimen of calcium and vitamin D would be considered. The prevention of osteopenia in patients with hemophilia is very cheaper than treatment of broken bones in hemophilia. Hence, implementation of bone density examination as part of the ITI protocols will be beneficial for both patients and health provider systems.

On the other hand, it would be expected that hemophilia to be considered as a risk factor in Frax criteria assessment tool. As a part of the ITI protocols, it is a good idea and essential to perform bone mineral density scans and provide calcium, vitamin D supplements, or bisphosphonate and anti-RANKL as protective drugs to the patients. Finally, assessment of BMD before and after ITI therapy for patients with hemophilia and inhibitor is recommended.

Footnotes

Authors’ Note

Z.R. gave idea; extracted and reviewed the piece of literatures, concluded of the findings, revised, and approved final draft of the manuscript. H.M. searched the medical search engines, extracted, and reviewed the literature, concluded of the findings, and wrote the primary version of draft.

Acknowledgments

The authors would like to thank the Mashhad University of Medical Sciences for financial support.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Mashhad University of Medical Sciences [grant number of 951533].

ORCID iD

Hassan Mansouritorghabeh

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Clinical Care of Bone Health in Patients on the Immune Tolerance Induction’s Protocols With an Immunosuppressive Agent for Inhibitor Eradication in Hemophilia

Abstract

Keywords

Introduction

Inhibitors in Hemophilia

Susceptibility of Patients With Severe Hemophilia to Reduced Bone Density

Clinical Question

Method

The Strategy of Search

Results

What Does the Reviewing of the Evidence Conclude?

Discussion

Conclusion

Future Prospects

Footnotes

Authors’ Note

Acknowledgments

Declaration of Conflicting Interests

Funding

ORCID iD

References