- Email: [email protected]
Acquired factor VIII inhibitor in a patient with multiple sclerosis treated with interferon β-1a
Journal of Neuroimmunology 340 (2020) 577146
Contents lists available at ScienceDirect
Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim
Short communication
Acquired factor VIII inhibitor in a patient with multiple sclerosis treated with interferon β-1a
T
⁎
D. Pandyaa, , V. Hellersliab, E. Gettingsc a
Temple University Hospital, Department of Neurology, 3401 North Broad Street, Philadelphia, PA 19140, USA Temple University Hospital, Department of Pharmacy Practice, Philadelphia, PA 19140, USA c Temple University Hospital, Department of Neurology, Philadelphia, PA 19140, USA b
A R T I C LE I N FO
A B S T R A C T
Keywords: Factor VIII deficiency, acquired Multiple sclerosis Interferon beta 1a Th1 cell Th2 cell
Acquired Factor VIII inhibitor is a rare acquired clotting disorder which has been seen in the setting of particular medications, autoimmune disease, and malignancy. Reports of this disorder in patients receiving immunomodulatory therapies for multiple sclerosis are rare. We present a case of a 48 year-old woman with likely development of acquired Factor VIII inhibitor in the setting of interferon beta monotherapy for multiple sclerosis, and discuss the pathogenesis of this disorder which involves shifts in helper T cell populations and increased production of immunoglobulins.
1. Introduction Acquired Factor VIII inhibitor is a rare hemophilic disorder characterized by the formation of autoantibodies against clotting factor VIII. In the general population, incidence of this disorder has been found to be about 1.3 per million people per year (Collins et al., 2004), and bleeding patterns in acquired factor VIII inhibitor differ from bleeding patterns in congenital Hemophilia A. The mortality rate can be relatively high, ranging from 8% to 22% (Franchini et al., 2007). Although ~50% of cases do not have a known etiology, a meta-analysis of patients with acquired Factor VIII inhibitor found associations with the post-partum state, systemic autoimmune disease, malignancies, and certain medications including type I interferons (Delgado et al., 2003). In this case report, we present a patient with relapsing remitting multiple sclerosis (RRMS) treated with low dose interferon β-1a who developed acquired Factor VIII inhibitor. To our knowledge, this is the 4th case of acquired Factor VIII inhibitor suspected to be associated with treatment of MS and only the second associated with interferon β1a; the prior cases were associated with interferon β-1a (Kaloyannidis et al., 2004) and with alemtuzumab (Pisa et al., 2019; McCaughan et al., 2017). 2. Case report A 48-year-old woman with previously stable RRMS on interferon β1a developed spontaneous lower extremity bruising on her upper thighs
⁎
and lower abdomen. For one year prior she had reported easy and spontaneous bleeding along with bruising following strenuous exercise. She did not have a history of bleeding diathesis. Her other medications on presentation were duloxetine, cyclobenzaprine, and lorazepam. She was diagnosed with multiple sclerosis at the age of 44 based on the 2010 revised McDonald's criteria. She was started on low dose interferon β-1a (weekly intramuscular injections of 30 micrograms) shortly after diagnosis and was clinically and radiologically stable. She had no history of malignancy or systemic autoimmune disease. Her non-interferon medications were not considered likely to have contributed to her bleeding. She was found to have a prolonged PTT (> 50 s). In light of her elevated PTT and history of bruising, an antinuclear antibody (ANA) test to rule out a lupus anticoagulant and a factor VIII panel were ordered. The ANA test was negative, however the factor VIII panel revealed a markedly reduced factor VIII activity at 4% and elevated factor VIII antibody titer of 7.8 Bethesda units (Table 1). Using this standardized testing, the patient was presumed to have factor VIII inhibitor (Kruse-Jarres et al., 2017). The patient's interferon β-1a was immediately discontinued and she was started on prednisone and cyclophosphamide to treat the suspected inhibitor. The patient was compliant with these medications, and following discontinuation of interferon β-1a there was an absence of new bleeds and normalization of her PTT (Fig. 1). However approximately one month after this regimen was started, she presented to the emergency room with black tarry stools. In the setting of this episode of repeat bleeding, cyclophosphamide
Corresponding author. E-mail address: [email protected] (D. Pandya).
https://doi.org/10.1016/j.jneuroim.2020.577146 Received 19 August 2019; Received in revised form 7 January 2020; Accepted 8 January 2020 0165-5728/ © 2020 Elsevier B.V. All rights reserved.
Journal of Neuroimmunology 340 (2020) 577146
D. Pandya, et al.
Table 1 Results of factor VIII panel and Bethesda assay before and after discontinuation of interferon β-1a.
APPT 1:1 Normal Plasma APPT 1:1 Mix Saline APTT 1:1 NP MIX, 60 MIN INCUB. Factor VIII Activity Factor VIII Bethesda Titer
Ref range & units
At presentation
Two weeks after discontinuation of interferon beta-1a
Four months after discontinuation of interferon beta-1a
23.4–36.4 s 0.0–37.0 s 23.4–36.4 s
34.9 53.9 41.8
30.2 40 33.6
26.4 43.1 –
50–150% 0.0–0.8 Bethesda units
4 7.8
14 1.6
131 –
The factor VIII panel utilizes PTT mixing studies and evaluates factor VIII activity in the serum. If these initial screening tests are positive, a reflex Bethesda assay is performed which can assess the level of factor VIII inhibitor. The Bethesda assay was designed specifically for this purpose, particularly in hemophiliac patients. An ELISA does exist to detect this molecule, but this test is less commonly utilized. Bolded values are abnormal (elevated).
Fig. 1. Serial PTT values in relation to use and discontinuation of interferon β-1a, along with other immunomodulatory therapies.
aforementioned wide array of actions. Let us analyze the possible ways in which interferon β could promote an immune state in which Factor VIII inhibitor could arise. Given that the formation of autoantibodies is a B-cell-mediated process, the effects of interferon β on B-cells may be most critical in the pathogenesis of Factor VIII inhibitor. However the effects of interferon β on T-helper cells must first be examined. Interferon β has been shown to increase transcription of the cytokine IL-4 along with secretion of this and other cytokines (e.g. IL-5, IL-13) (Kozovska et al., 1999; Rudick et al., 1998). These cytokines cause a shift toward the Th2 population and away from Th1, important because Th2 cells promote humoral immunity whereas the Th1 population promotes a cytotoxic response. IL-4 is a key cytokine as it serves multiple roles as 1) a stimulatory molecule for B cells, 2) a positive feedback molecule for Th2 cells, and 3) an inhibitor (along with TGF β) of differentiation of Th1 cells (Chen et al., 1994; Choi and Reiser, 1998). Interferon β also increases levels of CD 86+ B cells which stimulate Th2 cell proliferation, and possibly decreases CD 80+ B cells which otherwise would increase numbers of Th1 cells (Huang et al., 2013; Ramgolam et al., 2011). In this way it further reinforces humoral immunity and raises the likelihood of autoantibody production. Interferon β has also been shown to increase levels of B cell activating factor (BAFF), which activates B cells to produce immunoglobulin (Krumbholz et al., 2008). Through these more direct effects on B cells, we can see how conditions such as Factor VIII inhibitor may arise through use of Type I interferons. Of note, there have been case reports throughout recent decades of development of Factor VIII inhibitor with the use of
was discontinued. The patient was started on rituximab at 375 mg/m2 weekly for four total doses. Following rituximab treatment, factor VIII activity rebounded to 131% and she had no further bleeding. After completion of rituximab, glatiramer acetate was initiated and she has been maintained on this medication. The patient's RRMS has since been well-controlled with both clinical and radiologic stability and she has not had any recurrence of her factor VIII inhibitor.
3. Pathophysiology/discussion Formation of autoantibodies to Factor VIII has been reported in malignancy, autoimmune disease and in response to the use of other medications (Sallah and Wan, 2001a; Meiklejohn and Watson, 2001; Trotta et al., 1999; Sallah and Wan, 2001b). While the pathogenesis of these autoantibodies is not fully understood, a review of literature indicates some possible mechanisms. Type I (α and β) interferons have a myriad of effects, both stimulatory and suppressive, on the regulation of the immune system. They are highly influential factors in processes ranging from immune cell differentiation to transcriptional and translational regulation of various receptors and ligands. Both interferon α and interferon β operate through the canonical IFNAR-JAK-STAT pathway, in which they are ligands to a heterodimeric interferon receptor (IFNAR) with which binding activates the Janus kinase (JAK) and subsequently the signal transducer and activator of transcription (STAT) (Ivashkiv and Donlin, 2014). Ultimately this pathway leads to transcription of interferon-stimulated genes, and downstream gene products are effectors of the 2
Journal of Neuroimmunology 340 (2020) 577146
D. Pandya, et al.
interferon α, commonly in the setting of its use in hepatitis and cancer (e.g. Hodgkin's lymphoma) (Regina et al., 2001). Both Type 1 interferons (α and β) exhibit similar immune mechanisms resulting in a shift toward humoral immunity and a risk for antibody mediated disease. In addition to Factor VIII inhibitor, interferon use has been associated with the development of other autoimmune disorders. Case reports implicate interferon β in the development of disorders such as ADAMTS13 deficiency and thrombotic microangiopathy (Orvain et al., 2014; Nishio et al., 2016) and interferon α in disorders such as AIHA and autoimmune thyroiditis (Andriani et al., 1996; Prummel and Laurberg, 2003). Increased humoral immunity under these circumstances could be pathological, leading to production of autoantibodies (Han et al., 2015). This pathophysiology has been suggested in case reports involving the use of type I interferons in other antibody mediated diseases such as neuromyelitis optica spectrum disorder (NMOSD) (Palace et al., 2010; Kim et al., 2012). Finally, the possibility that MS itself could be the etiology of Factor VIII inhibitor should be considered. The production of autoantibodies is commonplace in a number of autoimmune conditions, such as in SLE (ANA among many others) and NMO (AQP4, MOG). In regards to MS and comorbid autoimmunity, a systematic review has shown that the quality of current literature describing this phenomenon is mediocre and does not indicate a significant relationship (Marrie et al., 2015). However, a number of case reports demonstrate the presence of Factor VIII inhibitor in patients with infection, malignancy, or autoimmune illness and in the absence of immunomodulatory agents. This includes literature describing the development of autoantibodies against clotting factors in the setting of MS (Moake et al., 1976; Hoyle and Ludlam, 1987). Recent studies have implied an increased role of B cell physiology in MS, a departure from the long-held view that it is largely a T cell-driven illness (Wekerle, 2017). Taking this all into account, we must consider that reversal or improvement of Factor VIII pathology in many cases may be due less to discontinuation of interferon β (or other implicated therapies) and more attributable to the use of therapies which directly or indirectly target B cell populations (e.g. anti-CD20 drugs).
Chen, Y., Kuchroo, V.K., Inobe, J., Hafler, D.A., Weiner, H.L., 1994. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 265, 1237. Choi, P., Reiser, H., 1998. IL-4: role in disease and regulation of production. Clin. Exp. Immunol. 113, 317–319. Collins, P., Macartney, N., Davies, R., Lees, S., Giddings, J., Majer, R., 2004. A population based, unselected, consecutive cohort of patients with acquired haemophilia A. Br. J. Haematol. 124 (1), 86–90. Delgado, J., Jimenez-yuste, V., Hernandez-navarro, F., Villar, A., 2003. Acquired haemophilia: review and meta-analysis focused on therapy and prognostic factors. Br. J. Haematol. 121 (1), 21–35. Franchini, M., Capra, F., Nicolini, N., Veneri, D., Manzato, F., Baudo, F., et al., 2007. Drug-induced anti-factor VIII antibodies: a systematic review. Med. Sci. Monit. 13 RA55–RA61. Han, S., Zhuang, H., Shumyak, S., Yang, L., Reeves, W.H., 2015. Mechanisms of autoantibody production in systemic lupus erythematosus. Front. Immunol. 6, 228. Hoyle, C., Ludlam, C.A., 1987. Acquired factor VIII inhibitor associated with multiple sclerosis, successfully treated with porcine factor VIII. Thromb. Haemost. 57, 233. Huang, H., Ito, K., Dangond, F., Dhib-Jalbut, S., 2013. Effect of interferon beta-1a on B7.1 and B7.2 B-cell expression and its impact on T-cell proliferation. J. Neuroimmunol. 258 (1–2), 27–31. Ivashkiv, L.B., Donlin, L.T., 2014. Regulation of type I interferon responses. Nat. Rev. Immunol. 14, 36–49. Kaloyannidis, P., Sakellari, I., Fassas, A., et al., 2004. Acquired hemophilia-A in a patient with multiple sclerosis treated with autologous hematopoietic stem cell transplantation and interferon β-1a. Bone Marrow Transplant. 34, 187–188. Kim, S.-H., Kim, W., Li, X.F., Jung, I.-J., Kim, H.J., 2012. Does interferon beta treatment exacerbate neuromyelitis optica spectrum disorder? Mult. Scler. 18, 1480–1483. Kozovska, M.E., Hong, J., Zang, Y.C., Li, S., Rivera, V.M., Killian, J.M., Zhang, J.Z., 1999. Interferon beta induces T-helper 2 immune deviation in MS. Neurology 53, 1692–1697. Krumbholz, M., Faber, H., Steinmeyer, F., Hoffmann, L.A., Kumpfel, T., Pellkofer, H., Derfuss, T., Ionescu, C., Starck, M., Hafner, C., Hohlfeld, R., Meinl, E., 2008. Interferon-beta increases BAFF levels in multiple sclerosis: implications for B cell autoimmunity. Brain 131, 1455–1463. Kruse-Jarres, R., et al., 2017. Acquired hemophilia A: updated review of evidence and treatment guidance. Am. J. Hematol. 92, 695–705. Marrie, R.A., Reider, N., Cohen, J., Stuve, O., Sorensen, P.S., Cutter, G., et al., 2015. A systematic review of the incidence and prevalence of autoimmune disease in multiple sclerosis. Mult. Scler. 21 (3), 282–293. McCaughan, G., Massey, J., Sutton, I., et al., 2017. Acquired haemophilia A complicating alemtuzumab therapy for multiple sclerosis. Case Rep. 2017 bcr-2017-223016. Meiklejohn, D.J., Watson, H.G., 2001. Acquired haemophilia in association with organspecific autoimmune disease. Haemophilia 7, 523–525. Moake, J.L., Kent, C.J., Meta, L.D., Wright, L.C., 1976. Circulating IgG antibodies against factors IX and VIII in multiple sclerosis. Acta Haematol. 55, 53–59. Nishio, H., Tsukamoto, T., Matsubara, T., Okada, Y., Takahashi, R., Yanagita, M., 2016. Thrombotic microangiopathy caused by interferon beta-1b for multiple sclerosis: a case report. CEN Case Rep. 5, 179–183. Orvain, C., Augusto, J.F., Besson, V., Marc, G., Coppo, P., Subra, J.F., et al., 2014. Thrombotic microangiopathy due to acquired ADAMTS13 deficiency in a patient receiving interferon-beta treatment for multiple sclerosis. Int. Urol. Nephrol. 46, 239–242. Palace, J., Leite, M.I., Nairne, A., Vincent, A., 2010. Interferon Beta treatment in neuromyelitis optica: increase in relapses and aquaporin 4 antibody titers. Arch. Neurol. 67, 1016–1017. Pisa, M., Della Valle, P., Coluccia, A., Martinelli, V., Comi, G., D’Angelo, A., Moiola, L., 2019. Acquired haemophilia A as a secondary autoimmune disease after alemtuzumab treatment in multiple sclerosis: a case report. Mult. Scler. Relat. Disord. 403–405. Prummel, M.F., Laurberg, P., 2003. Interferon-alpha and autoimmune thyroid disease. Thyroid 13, 547–551. Ramgolam, V.S., Sha, Y., Marcus, K.L., Choudhary, N., Troiani, L., Chopra, M., MarkovicPlese, S., 2011. B cells as a therapeutic target for IFN-beta in relapsing-remitting multiple sclerosis. J. Immunol. 186 (7), 4518–4526. Regina, S., Colombat, P., Fimbel, B., Guerois, C., Gruel, Y., 2001. Acquired inhibitor to factor VIII in a patient with Hodgkin’s disease following treatment with interferonalpha. Haemophilia 7 (5), 526–527. Rudick, R.A., Ransohoff, R.M., Lee, J.C., Peppler, R., Yu, M., Mathisen, P.M., Tuohy, V.K., 1998. In vivo effects of interferon β-1a on immunosuppressive cytokines in multiple sclerosis. Neurology 50, 1294–1300. Sallah, S., Wan, J.Y., 2001a. Inhibitors against factor VIII associated with the use of interferon-alpha and fludarabine. Thromb. Haemost. 86 (4), 1119–1121. Sallah, S., Wan, J.Y., 2001b. Inhibitors against factor VIII in patients with cancer. Cancer 91, 1067–1074. Trotta, F., Bajocchi, G., La Corte, R., et al., 1999. Long-lasting remission and successful treatment of acquired factor VIII inhibitors using cyclophosphamide in a patient with systemic lupus erythematosus. Rheumatology 38, 1007–1009. Wekerle, H., 2017. B cells in multiple sclerosis. Autoimmunity 50, 57–60.
4. Conclusion The development of Factor VIII inhibitor in this patient may be due to one of a number of causes. From the possibility of its development as a stochastic event, to the formation of autoantibodies in the neuroinflammatory milieu in a patient with multiple sclerosis, varying players can be implicated. However, given the clinical history of this patient, with cessation of bleeding and normalization of pertinent labs after discontinuation of the agent, interferon beta β-1a usage represents the likeliest culprit. The patient has remained stable and without any recurrence of bleeding after discontinuation of interferon β-1a. This case emphasizes the importance of awareness of possible consequences of the use of type I interferons. A newly elevated PTT and/or evidence of new bleeding in a patient on this class of medication should prompt the provider to further investigate the possibility of an acquired coagulopathy and to have a low threshold for termination of this therapy and initiation of an alternate immunomodulatory regimen. References Andriani, A., Bibas, M., Callea, V., De Renzo, A., Chiurazzi, F., Marcenò, R., Musto, P., Rotoli, B., 1996. Autoimmune haemolytic anemia during alpha interferon treatment in nine patients with hematological diseases. Haematologica 81, 258–260.
3
Contents lists available at ScienceDirect
Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim
Short communication
Acquired factor VIII inhibitor in a patient with multiple sclerosis treated with interferon β-1a
T
⁎
D. Pandyaa, , V. Hellersliab, E. Gettingsc a
Temple University Hospital, Department of Neurology, 3401 North Broad Street, Philadelphia, PA 19140, USA Temple University Hospital, Department of Pharmacy Practice, Philadelphia, PA 19140, USA c Temple University Hospital, Department of Neurology, Philadelphia, PA 19140, USA b
A R T I C LE I N FO
A B S T R A C T
Keywords: Factor VIII deficiency, acquired Multiple sclerosis Interferon beta 1a Th1 cell Th2 cell
Acquired Factor VIII inhibitor is a rare acquired clotting disorder which has been seen in the setting of particular medications, autoimmune disease, and malignancy. Reports of this disorder in patients receiving immunomodulatory therapies for multiple sclerosis are rare. We present a case of a 48 year-old woman with likely development of acquired Factor VIII inhibitor in the setting of interferon beta monotherapy for multiple sclerosis, and discuss the pathogenesis of this disorder which involves shifts in helper T cell populations and increased production of immunoglobulins.
1. Introduction Acquired Factor VIII inhibitor is a rare hemophilic disorder characterized by the formation of autoantibodies against clotting factor VIII. In the general population, incidence of this disorder has been found to be about 1.3 per million people per year (Collins et al., 2004), and bleeding patterns in acquired factor VIII inhibitor differ from bleeding patterns in congenital Hemophilia A. The mortality rate can be relatively high, ranging from 8% to 22% (Franchini et al., 2007). Although ~50% of cases do not have a known etiology, a meta-analysis of patients with acquired Factor VIII inhibitor found associations with the post-partum state, systemic autoimmune disease, malignancies, and certain medications including type I interferons (Delgado et al., 2003). In this case report, we present a patient with relapsing remitting multiple sclerosis (RRMS) treated with low dose interferon β-1a who developed acquired Factor VIII inhibitor. To our knowledge, this is the 4th case of acquired Factor VIII inhibitor suspected to be associated with treatment of MS and only the second associated with interferon β1a; the prior cases were associated with interferon β-1a (Kaloyannidis et al., 2004) and with alemtuzumab (Pisa et al., 2019; McCaughan et al., 2017). 2. Case report A 48-year-old woman with previously stable RRMS on interferon β1a developed spontaneous lower extremity bruising on her upper thighs
⁎
and lower abdomen. For one year prior she had reported easy and spontaneous bleeding along with bruising following strenuous exercise. She did not have a history of bleeding diathesis. Her other medications on presentation were duloxetine, cyclobenzaprine, and lorazepam. She was diagnosed with multiple sclerosis at the age of 44 based on the 2010 revised McDonald's criteria. She was started on low dose interferon β-1a (weekly intramuscular injections of 30 micrograms) shortly after diagnosis and was clinically and radiologically stable. She had no history of malignancy or systemic autoimmune disease. Her non-interferon medications were not considered likely to have contributed to her bleeding. She was found to have a prolonged PTT (> 50 s). In light of her elevated PTT and history of bruising, an antinuclear antibody (ANA) test to rule out a lupus anticoagulant and a factor VIII panel were ordered. The ANA test was negative, however the factor VIII panel revealed a markedly reduced factor VIII activity at 4% and elevated factor VIII antibody titer of 7.8 Bethesda units (Table 1). Using this standardized testing, the patient was presumed to have factor VIII inhibitor (Kruse-Jarres et al., 2017). The patient's interferon β-1a was immediately discontinued and she was started on prednisone and cyclophosphamide to treat the suspected inhibitor. The patient was compliant with these medications, and following discontinuation of interferon β-1a there was an absence of new bleeds and normalization of her PTT (Fig. 1). However approximately one month after this regimen was started, she presented to the emergency room with black tarry stools. In the setting of this episode of repeat bleeding, cyclophosphamide
Corresponding author. E-mail address: [email protected] (D. Pandya).
https://doi.org/10.1016/j.jneuroim.2020.577146 Received 19 August 2019; Received in revised form 7 January 2020; Accepted 8 January 2020 0165-5728/ © 2020 Elsevier B.V. All rights reserved.
Journal of Neuroimmunology 340 (2020) 577146
D. Pandya, et al.
Table 1 Results of factor VIII panel and Bethesda assay before and after discontinuation of interferon β-1a.
APPT 1:1 Normal Plasma APPT 1:1 Mix Saline APTT 1:1 NP MIX, 60 MIN INCUB. Factor VIII Activity Factor VIII Bethesda Titer
Ref range & units
At presentation
Two weeks after discontinuation of interferon beta-1a
Four months after discontinuation of interferon beta-1a
23.4–36.4 s 0.0–37.0 s 23.4–36.4 s
34.9 53.9 41.8
30.2 40 33.6
26.4 43.1 –
50–150% 0.0–0.8 Bethesda units
4 7.8
14 1.6
131 –
The factor VIII panel utilizes PTT mixing studies and evaluates factor VIII activity in the serum. If these initial screening tests are positive, a reflex Bethesda assay is performed which can assess the level of factor VIII inhibitor. The Bethesda assay was designed specifically for this purpose, particularly in hemophiliac patients. An ELISA does exist to detect this molecule, but this test is less commonly utilized. Bolded values are abnormal (elevated).
Fig. 1. Serial PTT values in relation to use and discontinuation of interferon β-1a, along with other immunomodulatory therapies.
aforementioned wide array of actions. Let us analyze the possible ways in which interferon β could promote an immune state in which Factor VIII inhibitor could arise. Given that the formation of autoantibodies is a B-cell-mediated process, the effects of interferon β on B-cells may be most critical in the pathogenesis of Factor VIII inhibitor. However the effects of interferon β on T-helper cells must first be examined. Interferon β has been shown to increase transcription of the cytokine IL-4 along with secretion of this and other cytokines (e.g. IL-5, IL-13) (Kozovska et al., 1999; Rudick et al., 1998). These cytokines cause a shift toward the Th2 population and away from Th1, important because Th2 cells promote humoral immunity whereas the Th1 population promotes a cytotoxic response. IL-4 is a key cytokine as it serves multiple roles as 1) a stimulatory molecule for B cells, 2) a positive feedback molecule for Th2 cells, and 3) an inhibitor (along with TGF β) of differentiation of Th1 cells (Chen et al., 1994; Choi and Reiser, 1998). Interferon β also increases levels of CD 86+ B cells which stimulate Th2 cell proliferation, and possibly decreases CD 80+ B cells which otherwise would increase numbers of Th1 cells (Huang et al., 2013; Ramgolam et al., 2011). In this way it further reinforces humoral immunity and raises the likelihood of autoantibody production. Interferon β has also been shown to increase levels of B cell activating factor (BAFF), which activates B cells to produce immunoglobulin (Krumbholz et al., 2008). Through these more direct effects on B cells, we can see how conditions such as Factor VIII inhibitor may arise through use of Type I interferons. Of note, there have been case reports throughout recent decades of development of Factor VIII inhibitor with the use of
was discontinued. The patient was started on rituximab at 375 mg/m2 weekly for four total doses. Following rituximab treatment, factor VIII activity rebounded to 131% and she had no further bleeding. After completion of rituximab, glatiramer acetate was initiated and she has been maintained on this medication. The patient's RRMS has since been well-controlled with both clinical and radiologic stability and she has not had any recurrence of her factor VIII inhibitor.
3. Pathophysiology/discussion Formation of autoantibodies to Factor VIII has been reported in malignancy, autoimmune disease and in response to the use of other medications (Sallah and Wan, 2001a; Meiklejohn and Watson, 2001; Trotta et al., 1999; Sallah and Wan, 2001b). While the pathogenesis of these autoantibodies is not fully understood, a review of literature indicates some possible mechanisms. Type I (α and β) interferons have a myriad of effects, both stimulatory and suppressive, on the regulation of the immune system. They are highly influential factors in processes ranging from immune cell differentiation to transcriptional and translational regulation of various receptors and ligands. Both interferon α and interferon β operate through the canonical IFNAR-JAK-STAT pathway, in which they are ligands to a heterodimeric interferon receptor (IFNAR) with which binding activates the Janus kinase (JAK) and subsequently the signal transducer and activator of transcription (STAT) (Ivashkiv and Donlin, 2014). Ultimately this pathway leads to transcription of interferon-stimulated genes, and downstream gene products are effectors of the 2
Journal of Neuroimmunology 340 (2020) 577146
D. Pandya, et al.
interferon α, commonly in the setting of its use in hepatitis and cancer (e.g. Hodgkin's lymphoma) (Regina et al., 2001). Both Type 1 interferons (α and β) exhibit similar immune mechanisms resulting in a shift toward humoral immunity and a risk for antibody mediated disease. In addition to Factor VIII inhibitor, interferon use has been associated with the development of other autoimmune disorders. Case reports implicate interferon β in the development of disorders such as ADAMTS13 deficiency and thrombotic microangiopathy (Orvain et al., 2014; Nishio et al., 2016) and interferon α in disorders such as AIHA and autoimmune thyroiditis (Andriani et al., 1996; Prummel and Laurberg, 2003). Increased humoral immunity under these circumstances could be pathological, leading to production of autoantibodies (Han et al., 2015). This pathophysiology has been suggested in case reports involving the use of type I interferons in other antibody mediated diseases such as neuromyelitis optica spectrum disorder (NMOSD) (Palace et al., 2010; Kim et al., 2012). Finally, the possibility that MS itself could be the etiology of Factor VIII inhibitor should be considered. The production of autoantibodies is commonplace in a number of autoimmune conditions, such as in SLE (ANA among many others) and NMO (AQP4, MOG). In regards to MS and comorbid autoimmunity, a systematic review has shown that the quality of current literature describing this phenomenon is mediocre and does not indicate a significant relationship (Marrie et al., 2015). However, a number of case reports demonstrate the presence of Factor VIII inhibitor in patients with infection, malignancy, or autoimmune illness and in the absence of immunomodulatory agents. This includes literature describing the development of autoantibodies against clotting factors in the setting of MS (Moake et al., 1976; Hoyle and Ludlam, 1987). Recent studies have implied an increased role of B cell physiology in MS, a departure from the long-held view that it is largely a T cell-driven illness (Wekerle, 2017). Taking this all into account, we must consider that reversal or improvement of Factor VIII pathology in many cases may be due less to discontinuation of interferon β (or other implicated therapies) and more attributable to the use of therapies which directly or indirectly target B cell populations (e.g. anti-CD20 drugs).
Chen, Y., Kuchroo, V.K., Inobe, J., Hafler, D.A., Weiner, H.L., 1994. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 265, 1237. Choi, P., Reiser, H., 1998. IL-4: role in disease and regulation of production. Clin. Exp. Immunol. 113, 317–319. Collins, P., Macartney, N., Davies, R., Lees, S., Giddings, J., Majer, R., 2004. A population based, unselected, consecutive cohort of patients with acquired haemophilia A. Br. J. Haematol. 124 (1), 86–90. Delgado, J., Jimenez-yuste, V., Hernandez-navarro, F., Villar, A., 2003. Acquired haemophilia: review and meta-analysis focused on therapy and prognostic factors. Br. J. Haematol. 121 (1), 21–35. Franchini, M., Capra, F., Nicolini, N., Veneri, D., Manzato, F., Baudo, F., et al., 2007. Drug-induced anti-factor VIII antibodies: a systematic review. Med. Sci. Monit. 13 RA55–RA61. Han, S., Zhuang, H., Shumyak, S., Yang, L., Reeves, W.H., 2015. Mechanisms of autoantibody production in systemic lupus erythematosus. Front. Immunol. 6, 228. Hoyle, C., Ludlam, C.A., 1987. Acquired factor VIII inhibitor associated with multiple sclerosis, successfully treated with porcine factor VIII. Thromb. Haemost. 57, 233. Huang, H., Ito, K., Dangond, F., Dhib-Jalbut, S., 2013. Effect of interferon beta-1a on B7.1 and B7.2 B-cell expression and its impact on T-cell proliferation. J. Neuroimmunol. 258 (1–2), 27–31. Ivashkiv, L.B., Donlin, L.T., 2014. Regulation of type I interferon responses. Nat. Rev. Immunol. 14, 36–49. Kaloyannidis, P., Sakellari, I., Fassas, A., et al., 2004. Acquired hemophilia-A in a patient with multiple sclerosis treated with autologous hematopoietic stem cell transplantation and interferon β-1a. Bone Marrow Transplant. 34, 187–188. Kim, S.-H., Kim, W., Li, X.F., Jung, I.-J., Kim, H.J., 2012. Does interferon beta treatment exacerbate neuromyelitis optica spectrum disorder? Mult. Scler. 18, 1480–1483. 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4. Conclusion The development of Factor VIII inhibitor in this patient may be due to one of a number of causes. From the possibility of its development as a stochastic event, to the formation of autoantibodies in the neuroinflammatory milieu in a patient with multiple sclerosis, varying players can be implicated. However, given the clinical history of this patient, with cessation of bleeding and normalization of pertinent labs after discontinuation of the agent, interferon beta β-1a usage represents the likeliest culprit. The patient has remained stable and without any recurrence of bleeding after discontinuation of interferon β-1a. This case emphasizes the importance of awareness of possible consequences of the use of type I interferons. A newly elevated PTT and/or evidence of new bleeding in a patient on this class of medication should prompt the provider to further investigate the possibility of an acquired coagulopathy and to have a low threshold for termination of this therapy and initiation of an alternate immunomodulatory regimen. References Andriani, A., Bibas, M., Callea, V., De Renzo, A., Chiurazzi, F., Marcenò, R., Musto, P., Rotoli, B., 1996. Autoimmune haemolytic anemia during alpha interferon treatment in nine patients with hematological diseases. Haematologica 81, 258–260.
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