- Email: [email protected]
Rebound syndrome after teriflunomide cessation in a patient with multiple sclerosis
Journal of the Neurological Sciences 380 (2017) 79–81
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Rebound syndrome after teriflunomide cessation in a patient with multiple sclerosis Keywords: Multiple sclerosis Teriflunomide Rebound
1. Introduction A rebound syndrome (RS) has been reported upon withdrawal of disease modifying therapies in patients with relapsing remitting multiple sclerosis (RRMS). It is defined as return of disease activity exceeding pre-drug activity around 8–24 weeks after drug cessation [1–2]. It is usually not related to prior disease course, and manifests as severe clinical and radiological activity. Rebound or withdrawal syndrome has been described with natalizumab and fingolimod [3, 4]. Teriflunomide is a novel oral agent recently approved for the treatment of RRMS [5]. It works primarily by inhibiting a key mitochondrial enzyme, dihydroorotate-dehydrogenase (DHODH), leading to decreased synthesis of pyrimidine in rapidly proliferating cells such as T and B lymphocytes in MS. Its beneficial effect in controlling disease activity in MS is not fully understood, but might be through decreasing the inflammatory response to auto-antigens [6]. Rebound disease activity after teriflunomide or leflunomide withdrawal has not been previously reported. We describe here the case of a 38 year old woman with RRMS, who was clinically stable for 8 years, but developed a severe clinical and radiological RS12 weeks after discontinuing teriflunomide. 2. Case This is a 38 year old woman with a 9-year history of RRMS. She had no previous relevant medical conditions, but reported a strong family history of autoimmune disorders including Behcet's disease, Celiac disease and hemolytic anemia in 3 different siblings. Her first relapse in May 2008 consisted of gait imbalance, diplopia, dysarthria, dysphagia, and right hemiparesis. She recovered fully following a 5-daycourse of high dose IV-steroids. A brain MRI in June 2008 showed a high lesion load with multiple enhancing lesions. CSF studies revealed 15 white blood cells, multiple oligoclonal bands and an IgG index of 1.54. She was started on subcutaneous interferon-beta-1a 44 μg three times weekly, and a follow-up MRI in October 2008 showed no new enhancing lesions with significant decrease in lesion load. She developed a second relapse in 2009 with bilateral lower extremities numbness resulting in an EDSS of 3.0 but had a full recovery following a course of high dose IV-steroids. A new brain MRI revealed 1 new non-enhancing lesion in the right temporal lobe.
http://dx.doi.org/10.1016/j.jns.2017.07.014 0022-510X/© 2017 Elsevier B.V. All rights reserved.
Her EDSS stabilized at 1.5, and she had no further relapses or new lesions on her annual brain MRI's for the following 7 years. In November 2015 she was switched to teriflunomide due to persistent flu-like symptoms and injection site reactions but developed significant side effects including menorrhagia, severe and persistent hair loss, and gingival bleeding. We advised her to switch to Dimethyl fumarate but she elected to remain off-treatment since she has been clinically and radiologically stable for the past 7 years. She discontinued teriflunomide in October 2016. Her white blood count (WBC) at that point was 5900/mm 3 with an absolute lymphocyte count (ALC) of 1650/mm 3 . Her brain MRI that same month was still stable with no new or enhancing lesions. On the 25th of January 2017, she developed right lower facial numbness, bilateral lower extremities numbness, and gait imbalance leading to an EDSS increase up to 3.5. She received a 5 day course of IV methylprednisolone at a dose of 1 g/day but showed minimal improvement unlike her previous relapses. A month later, her condition worsened with increased lower extremities numbness and weakness. Her EDSS increased to 6 and she was unable to walk without unilateral support. An MRI of brain and spine revealed multiple new lesions compared to the last MRI performed in October 2016 with more than 11 ring enhancing lesions (Fig. 1). Due to the significant clinical and radiological worsening, additional serological and CSF studies were obtained to rule out any concomitant infectious or inflammatory disorders. CSF studies revealed again multiple oligoclonal bands with an IgG index of 0.61, a glucose of 69 mg/dl and 6 white blood cells. Qualitative CSF multiplexed PCR for tuberculosis, Escherichia Coli/K, Haemophilus influenza, Listeria monocytogenes, Neisseria meningitis, Streptococcus agalatia, Streptococcus pneumonia, Cytomegalovirus, Enterovirus, Herpes simplex virus 1, Herpes simplex virus 2, Human virus 6,Human parechovirus, Varicella zoster virus, and Cryptococcus neoformans/gattii was negative. Serological studies including Brucella direct and indirect antibodies, ANA, Anti-SSA, Anti-SSB, anti-endomysial antibodies, anti-cardiolipin antibodies, and antiaquaporin 4 antibodies were all normal. Her symptoms improved significantly after a second course of IV steroids and her EDSS decreased to 1.5 by March 2017. Her WBC at that point was 5300/ mm 3 with an absolute lymphocyte count (ALC) of 1590/mm 3. She was kept on oral prednisone 60 mg daily for 2 weeks followed by 2 Rituximab (1 g) infusions separated by 2 weeks. Three months following her last rituximab infusion the patient had fully recovered with an EDSS of 1.5.
3. Discussion We report a patient with severe disease reactivation 12 weeks after cessation of teriflunomide therapy, consistent with the definition of RS. To the best of our knowledge this is the first report of RS following discontinuation of teriflunomide.
80
Letter to the Editor
Fig. 1. A - Axial brain fluid-attenuated inversion recovery (FLAIR) images 4 weeks before treatment discontinuation showing radiological stability (14/10/2016) compared to previous MRIs. B - Axial brain FLAIR images 12 weeks after stopping teriflunomide, showing new demyelinating lesions. C - Post-contrast brain T1 weighted images 12 weeks after ceasing teriflunomide showing new enhancing lesions. D - Cervical spine T2 and post-contrast cervical and dorsal spine T1 weighted images 12 weeks after stopping treatment showing multiple enhancing lesions at the level of C3, C4, C6, C7, T1, T, T6, T7, and T11.
With the introduction of new disease modifying therapies, the practice of switching medications in patients with MS is becoming more frequent. Severe disease reactivation during the washout period has been reported with natalizumab and fingolimod in around 10% of cases [1,4,7]. Such rebound phenomenon usually occurs between 4 and 24 weeks following drug cessation. The exact mechanism underlying RS is still not well understood but is thought to be a form of immune reconstitution inflammatory syndrome (IRIS) whereby the immune system recovers following withdrawal of the immunosuppressant resulting in a rebound effect to a higher level of inflammation than prior to treatment [8]. Teriflunomide selectively and reversibly inhibits the mitochondrial enzyme DHODH, resulting in reduced proliferation of activated T and B lymphocytes while sparing resting and slowly dividing cells [5]. Teriflunomide exerts also a cytostatic effect on stimulated lymphocytes in the periphery, reducing their availability to migrate into the central nervous system (CNS). As the pyrimidine demand of resting and slowly dividing cells (including memory lymphocytes) is met through the DHODH-independent salvage pathway, teriflunomide may preserve protective immunity [9]. The peripheral lymphocyte count decreases by around 15% during teriflunomide therapy while the total white blood count remains unaffected. As the median half-life of teriflunomide is 19 days, a 4–8-week wash-out period is needed after cessation [10]. The exact mechanism of RS in teriflunomide is not clear although a rapid restoration of cellular immunity following withdrawal of the drug seems likely. We postulate that rapid lymphocyte or lymphocyte subset proliferation and re-entry into the CNS after reactivation of the DHODH enzyme may trigger rebound inflammation. It is of note that our patient had a stable ALC during teriflunomide therapy and following its withdrawal. It is of interest that prior to drug discontinuation, our patient was stable on Interferon-Beta-1a then teriflunomide for almost 7 years without any relapses, disability progression or new lesions on MRI. Her last relapse which occurred while still on interferon was mild and predominantly sensory with a single new lesion on brain MRI. There were no noticeable differences in terms of clinical and radiological manifestations between our patient and the previously reported cases of RS on natalizumab and fingolimod. Similar to other patients with RS following discontinuation of fingolimod or natalizumab, our patient failed to respond to the first IV steroids course and kept worsening until she received a second course followed by maintenance on oral prednisone. Rebound syndrome in MS is probably a more widespread phenomenon than previously considered and may be associated
with therapeutic agents that have different mechanisms of action. Funding None. Conflict of Interest Bassem I Yamout, Marianne Said, Salem Hannoun, Maya Zeineddine, Joelle Massouh, and Samia J Khourydeclare that they have no conflict of interest. Acknowledgements None References [1] R.G. Beran, Y. Hegazi, R.S. Schwartz, D.J. Cordato, Rebound exacerbation multiple sclerosis following cessation of oral treatment, Mult. Scler. Relat. Dis. 2 (2013) 252–255. [2] J.B. Havla, H.L. Pellkofer, I. Meinl, L.A. Gerdes, R. Hohlfeld, T. Kümpfel, Rebound of disease activity after withdrawal of fingolimod (FTY720) treatment, Arch. Neurol. 69 (2012) 262–264. [3] A. Miravalle, R. Jensen, R.P. Kinkel, Immune reconstitution inflammatory syndrome in patients with multiple sclerosis following cessation of natalizumab therapy, Arch. Neurol. 68 (2011) 186–191. [4] S.E. Hatcher, E. Waubant, B. Nourbakhsh, E. Crabtree-Hartman, J.S. Graves, Rebound syndrome in patients with multiple sclerosis after cessation of fingolimod treatment, JAMA Neurol. 73 (2016) 790–794. [5] P. O'Connor, J. Wolinsky, C. Confavreux, et al., Randomized trial of oral teriflunomide for relapsing multiple sclerosis, NEJM 365 (2011) 1293–1303. [6] Y.D. Fragoso, J.B. Brooks, Leflunomide and teriflunomide: altering the metabolism of pyrimidines for the treatment of autoimmune diseases, Expert. Rev. Clin. Pharmacol. 8 (2015) 315–320. [7] F. Rinaldi, D. Seppi, M. Calabrese, P. Perini, P. Gallo, Switching therapy from natalizumab to fingolimod in relapsing–remitting multiple sclerosis: clinical and magnetic resonance imaging findings, Mult Scler. 18 (2012) 1640–1643. [8] I. Metz, E.W. Radue, A. Oterino, et al., Pathology of immune reconstitution inflammatory syndrome in multiple sclerosis with natalizumab-associated progressive multifocal leukoencephalopathy, Acta Neuropathol. 123 (2012) 235–245. [9] A. Bar-Or, H. Wiendl, B. Miller, et al., Randomized study of teriflunomide effects on immune responses to neoantigen and recall antigens, Neurol. Neuroimmunol. Neuroinflamm. 2 (2015) e70. [10] M.C. Claussen, T. Korn, Immune mechanisms of new therapeutic strategies in MS—Teriflunomide, Clin. Immunol. 142 (2012) 49–56.
Letter to the Editor
Bassem I. Yamout* Marianne Said Salem Hannoun Maya Zeineddine Joelle Massouh Samia J. Khoury Nehme and Therese Tohme Multiple Sclerosis Center, American University of Beirut Medical Center, Beirut, Lebanon *Corresponding author at: American University of Beirut Medical Center, Riad El-Solh 1107 2020, Beirut, Lebanon. E-mail address: [email protected] (B.I. Yamout). 2 June 2017 Available online 9 July 2017
81
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Rebound syndrome after teriflunomide cessation in a patient with multiple sclerosis Keywords: Multiple sclerosis Teriflunomide Rebound
1. Introduction A rebound syndrome (RS) has been reported upon withdrawal of disease modifying therapies in patients with relapsing remitting multiple sclerosis (RRMS). It is defined as return of disease activity exceeding pre-drug activity around 8–24 weeks after drug cessation [1–2]. It is usually not related to prior disease course, and manifests as severe clinical and radiological activity. Rebound or withdrawal syndrome has been described with natalizumab and fingolimod [3, 4]. Teriflunomide is a novel oral agent recently approved for the treatment of RRMS [5]. It works primarily by inhibiting a key mitochondrial enzyme, dihydroorotate-dehydrogenase (DHODH), leading to decreased synthesis of pyrimidine in rapidly proliferating cells such as T and B lymphocytes in MS. Its beneficial effect in controlling disease activity in MS is not fully understood, but might be through decreasing the inflammatory response to auto-antigens [6]. Rebound disease activity after teriflunomide or leflunomide withdrawal has not been previously reported. We describe here the case of a 38 year old woman with RRMS, who was clinically stable for 8 years, but developed a severe clinical and radiological RS12 weeks after discontinuing teriflunomide. 2. Case This is a 38 year old woman with a 9-year history of RRMS. She had no previous relevant medical conditions, but reported a strong family history of autoimmune disorders including Behcet's disease, Celiac disease and hemolytic anemia in 3 different siblings. Her first relapse in May 2008 consisted of gait imbalance, diplopia, dysarthria, dysphagia, and right hemiparesis. She recovered fully following a 5-daycourse of high dose IV-steroids. A brain MRI in June 2008 showed a high lesion load with multiple enhancing lesions. CSF studies revealed 15 white blood cells, multiple oligoclonal bands and an IgG index of 1.54. She was started on subcutaneous interferon-beta-1a 44 μg three times weekly, and a follow-up MRI in October 2008 showed no new enhancing lesions with significant decrease in lesion load. She developed a second relapse in 2009 with bilateral lower extremities numbness resulting in an EDSS of 3.0 but had a full recovery following a course of high dose IV-steroids. A new brain MRI revealed 1 new non-enhancing lesion in the right temporal lobe.
http://dx.doi.org/10.1016/j.jns.2017.07.014 0022-510X/© 2017 Elsevier B.V. All rights reserved.
Her EDSS stabilized at 1.5, and she had no further relapses or new lesions on her annual brain MRI's for the following 7 years. In November 2015 she was switched to teriflunomide due to persistent flu-like symptoms and injection site reactions but developed significant side effects including menorrhagia, severe and persistent hair loss, and gingival bleeding. We advised her to switch to Dimethyl fumarate but she elected to remain off-treatment since she has been clinically and radiologically stable for the past 7 years. She discontinued teriflunomide in October 2016. Her white blood count (WBC) at that point was 5900/mm 3 with an absolute lymphocyte count (ALC) of 1650/mm 3 . Her brain MRI that same month was still stable with no new or enhancing lesions. On the 25th of January 2017, she developed right lower facial numbness, bilateral lower extremities numbness, and gait imbalance leading to an EDSS increase up to 3.5. She received a 5 day course of IV methylprednisolone at a dose of 1 g/day but showed minimal improvement unlike her previous relapses. A month later, her condition worsened with increased lower extremities numbness and weakness. Her EDSS increased to 6 and she was unable to walk without unilateral support. An MRI of brain and spine revealed multiple new lesions compared to the last MRI performed in October 2016 with more than 11 ring enhancing lesions (Fig. 1). Due to the significant clinical and radiological worsening, additional serological and CSF studies were obtained to rule out any concomitant infectious or inflammatory disorders. CSF studies revealed again multiple oligoclonal bands with an IgG index of 0.61, a glucose of 69 mg/dl and 6 white blood cells. Qualitative CSF multiplexed PCR for tuberculosis, Escherichia Coli/K, Haemophilus influenza, Listeria monocytogenes, Neisseria meningitis, Streptococcus agalatia, Streptococcus pneumonia, Cytomegalovirus, Enterovirus, Herpes simplex virus 1, Herpes simplex virus 2, Human virus 6,Human parechovirus, Varicella zoster virus, and Cryptococcus neoformans/gattii was negative. Serological studies including Brucella direct and indirect antibodies, ANA, Anti-SSA, Anti-SSB, anti-endomysial antibodies, anti-cardiolipin antibodies, and antiaquaporin 4 antibodies were all normal. Her symptoms improved significantly after a second course of IV steroids and her EDSS decreased to 1.5 by March 2017. Her WBC at that point was 5300/ mm 3 with an absolute lymphocyte count (ALC) of 1590/mm 3. She was kept on oral prednisone 60 mg daily for 2 weeks followed by 2 Rituximab (1 g) infusions separated by 2 weeks. Three months following her last rituximab infusion the patient had fully recovered with an EDSS of 1.5.
3. Discussion We report a patient with severe disease reactivation 12 weeks after cessation of teriflunomide therapy, consistent with the definition of RS. To the best of our knowledge this is the first report of RS following discontinuation of teriflunomide.
80
Letter to the Editor
Fig. 1. A - Axial brain fluid-attenuated inversion recovery (FLAIR) images 4 weeks before treatment discontinuation showing radiological stability (14/10/2016) compared to previous MRIs. B - Axial brain FLAIR images 12 weeks after stopping teriflunomide, showing new demyelinating lesions. C - Post-contrast brain T1 weighted images 12 weeks after ceasing teriflunomide showing new enhancing lesions. D - Cervical spine T2 and post-contrast cervical and dorsal spine T1 weighted images 12 weeks after stopping treatment showing multiple enhancing lesions at the level of C3, C4, C6, C7, T1, T, T6, T7, and T11.
With the introduction of new disease modifying therapies, the practice of switching medications in patients with MS is becoming more frequent. Severe disease reactivation during the washout period has been reported with natalizumab and fingolimod in around 10% of cases [1,4,7]. Such rebound phenomenon usually occurs between 4 and 24 weeks following drug cessation. The exact mechanism underlying RS is still not well understood but is thought to be a form of immune reconstitution inflammatory syndrome (IRIS) whereby the immune system recovers following withdrawal of the immunosuppressant resulting in a rebound effect to a higher level of inflammation than prior to treatment [8]. Teriflunomide selectively and reversibly inhibits the mitochondrial enzyme DHODH, resulting in reduced proliferation of activated T and B lymphocytes while sparing resting and slowly dividing cells [5]. Teriflunomide exerts also a cytostatic effect on stimulated lymphocytes in the periphery, reducing their availability to migrate into the central nervous system (CNS). As the pyrimidine demand of resting and slowly dividing cells (including memory lymphocytes) is met through the DHODH-independent salvage pathway, teriflunomide may preserve protective immunity [9]. The peripheral lymphocyte count decreases by around 15% during teriflunomide therapy while the total white blood count remains unaffected. As the median half-life of teriflunomide is 19 days, a 4–8-week wash-out period is needed after cessation [10]. The exact mechanism of RS in teriflunomide is not clear although a rapid restoration of cellular immunity following withdrawal of the drug seems likely. We postulate that rapid lymphocyte or lymphocyte subset proliferation and re-entry into the CNS after reactivation of the DHODH enzyme may trigger rebound inflammation. It is of note that our patient had a stable ALC during teriflunomide therapy and following its withdrawal. It is of interest that prior to drug discontinuation, our patient was stable on Interferon-Beta-1a then teriflunomide for almost 7 years without any relapses, disability progression or new lesions on MRI. Her last relapse which occurred while still on interferon was mild and predominantly sensory with a single new lesion on brain MRI. There were no noticeable differences in terms of clinical and radiological manifestations between our patient and the previously reported cases of RS on natalizumab and fingolimod. Similar to other patients with RS following discontinuation of fingolimod or natalizumab, our patient failed to respond to the first IV steroids course and kept worsening until she received a second course followed by maintenance on oral prednisone. Rebound syndrome in MS is probably a more widespread phenomenon than previously considered and may be associated
with therapeutic agents that have different mechanisms of action. Funding None. Conflict of Interest Bassem I Yamout, Marianne Said, Salem Hannoun, Maya Zeineddine, Joelle Massouh, and Samia J Khourydeclare that they have no conflict of interest. Acknowledgements None References [1] R.G. Beran, Y. Hegazi, R.S. Schwartz, D.J. Cordato, Rebound exacerbation multiple sclerosis following cessation of oral treatment, Mult. Scler. Relat. Dis. 2 (2013) 252–255. [2] J.B. Havla, H.L. Pellkofer, I. Meinl, L.A. Gerdes, R. Hohlfeld, T. Kümpfel, Rebound of disease activity after withdrawal of fingolimod (FTY720) treatment, Arch. Neurol. 69 (2012) 262–264. [3] A. Miravalle, R. Jensen, R.P. Kinkel, Immune reconstitution inflammatory syndrome in patients with multiple sclerosis following cessation of natalizumab therapy, Arch. Neurol. 68 (2011) 186–191. [4] S.E. Hatcher, E. Waubant, B. Nourbakhsh, E. Crabtree-Hartman, J.S. Graves, Rebound syndrome in patients with multiple sclerosis after cessation of fingolimod treatment, JAMA Neurol. 73 (2016) 790–794. [5] P. O'Connor, J. Wolinsky, C. Confavreux, et al., Randomized trial of oral teriflunomide for relapsing multiple sclerosis, NEJM 365 (2011) 1293–1303. [6] Y.D. Fragoso, J.B. Brooks, Leflunomide and teriflunomide: altering the metabolism of pyrimidines for the treatment of autoimmune diseases, Expert. Rev. Clin. Pharmacol. 8 (2015) 315–320. [7] F. Rinaldi, D. Seppi, M. Calabrese, P. Perini, P. Gallo, Switching therapy from natalizumab to fingolimod in relapsing–remitting multiple sclerosis: clinical and magnetic resonance imaging findings, Mult Scler. 18 (2012) 1640–1643. [8] I. Metz, E.W. Radue, A. Oterino, et al., Pathology of immune reconstitution inflammatory syndrome in multiple sclerosis with natalizumab-associated progressive multifocal leukoencephalopathy, Acta Neuropathol. 123 (2012) 235–245. [9] A. Bar-Or, H. Wiendl, B. Miller, et al., Randomized study of teriflunomide effects on immune responses to neoantigen and recall antigens, Neurol. Neuroimmunol. Neuroinflamm. 2 (2015) e70. [10] M.C. Claussen, T. Korn, Immune mechanisms of new therapeutic strategies in MS—Teriflunomide, Clin. Immunol. 142 (2012) 49–56.
Letter to the Editor
Bassem I. Yamout* Marianne Said Salem Hannoun Maya Zeineddine Joelle Massouh Samia J. Khoury Nehme and Therese Tohme Multiple Sclerosis Center, American University of Beirut Medical Center, Beirut, Lebanon *Corresponding author at: American University of Beirut Medical Center, Riad El-Solh 1107 2020, Beirut, Lebanon. E-mail address: [email protected] (B.I. Yamout). 2 June 2017 Available online 9 July 2017
81