- Email: [email protected]
Rebound after discontinuation of teriflunomide in patients with multiple sclerosis: 2 case reports
Journal Pre-proof
Rebound after discontinuation of teriflunomide in patients with multiple sclerosis: 2 case reports ´ , R Lopez ´ A Fuerte-Hortigon Ru´ız , JD Guerra Hiraldo , ´ ´ ´ F Sanchez Fernandez , J Dotor Garc´ıa-Soto , L Paramo , ˜ , G Navarro-Mascarell , S Eichau JL Ruiz-Pena PII: DOI: Reference:
S2211-0348(20)30093-6 https://doi.org/10.1016/j.msard.2020.102017 MSARD 102017
To appear in:
Multiple Sclerosis and Related Disorders
Received date: Revised date: Accepted date:
3 January 2020 11 February 2020 21 February 2020
´ , ´ Please cite this article as: A Fuerte-Hortigon R Lopez Ru´ız , JD Guerra Hiraldo , ´ ´ ´ ˜ , G Navarro-Mascarell , F Sanchez Fernandez , J Dotor Garc´ıa-Soto , L Paramo , JL Ruiz-Pena S Eichau , Rebound after discontinuation of teriflunomide in patients with multiple sclerosis: 2 case reports, Multiple Sclerosis and Related Disorders (2020), doi: https://doi.org/10.1016/j.msard.2020.102017
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier B.V.
Highlights
Teriflunomide is an oral first-line therapy used in relapsing forms of MS
The washout period of teriflunomide may be accelerated by cholestyramine
Clearance of teriflunomide (<0.02µg/ml) are usually verified after washout period
Cases of MS relapse has been reported after the withdrawal of first-line therapies
Drug switching is possible after cholestyramine washout without level verification
Rebound after discontinuation of teriflunomide in patients with multiple sclerosis: 2 case reports Fuerte-Hortigón A1, López Ruíz R1, Guerra Hiraldo JD1, Sánchez Fernández F1, Dotor García-Soto J1, Páramo L1, RuizPeña JL1, Navarro-Mascarell G1, Eichau S1 1. Multiple Sclerosis Department. Virgen Macarena Hospital, Sevilla
Corresponding author: Alejandro Fuerte Hortigón. C/José Laguillo 29, 3rd portal, 4ºA [email protected] +34652524956 Conflicts of interest: The authors declare no conflicts of interest Funding: No funding has been received for this study.
Abstract: Teriflunomide is an oral first-line disease modifying treatment (DMT) for patients with relapsing-remitting multiple sclerosis (RRMS). It can take up to two years to achieve systemic clearance of teriflunomide to an acceptable level, but this washout period may be accelerated by administration of cholestyramine. Relapse of multiple sclerosis (MS) during washout of teriflunomide or other first-line DMT is not as common. We report two patients with RRMS who experienced a relapse after the accelerated elimination period (AEP) of teriflunomide and confirmation of negative plasmatic levels (<0.02µg/ml). In cases of risk of MS activity, we should not wait for teriflunomide negative plasmatic levels confirmation before starting the next DMT to reduce the risk of relapse. Keywords: Multiple Sclerosis, teriflunomide, accelerated elimination procedure, cholestyramine, tumefactive lesion Introduction Teriflunomide is an oral first-line disease modifying treatment (DMT) for patients with relapsing-remitting multiple sclerosis (RRMS). The main mechanism of action of teriflunomide is inhibition of the mitochondrial enzyme dihydroorotate-dehydrogenase (DHODH), precipitating a reduction of activated T and B lymphocytes1. It can take up to two years to achieve systemic clearance of teriflunomide to an acceptable level, but this washout period may be accelerated by administration of cholestyramine or activated charcoal for 11 days1. Relapse of multiple sclerosis (MS) is relatively common following cessation of high-efficacy disease modifying treatment (DMT) such as Natalizumab or Fingolimod, but relapses during washout of teriflunomide or other first-line DMT is not as common. However, recent cases of relapse of disease have been reported after the withdrawal of dimethyl fumarate2 and teriflunomide3. Here we describe two patients with MS relapse during the washout procedure of teriflunomide and after confirmation of plasma levels < 0.02 µg/ml. These patents showed worsening of disability and residual neurological sequelae despite steroid treatment.
Case 1 34-year-old male diagnosed with RRMS in 2001. Upon presentation, his expanded disability status scale (EDSS) estimate was 1.0. He was first treated with interferon-beta 1a (subcutaneous) 44 micrograms three times per week. Over the next 14 years, there was no clinical attack or MRI disease activity; however, in January 2017 it was decided to switch to teriflunomide due to injection-site erythema. He started teriflunomide in May 2017. After five months, the patient had developed left optic neuritis (ON). Visual acuity was 0.6 (corrected) and the EDSS score 1.5. He received treatment with corticoids with no improvement. In August 2018, teriflunomide was discontinued due to
persistent MRI activity in both 2017 and 2018. Washout procedure with cholestyramine was started at this time. During the washout period and after confirmation of teriflunomide plasma levels < 0.02 µg/ml (September 2018), the patient experienced a severe relapse with instability and right hemicorporal hypoesthesia and his EDSS score rose to 3. MRI showed four new, gadolinium-enhanced lesions, one of which was of a pseudotumoral character in the left parietal lobe (figure 1 [arrow]). The patient received methylprednisolone 1000 mg daily for 5 days without total clinical improvement.
Image 1 FLAIR coronal image (A) and T2 axial image (B), June 2018, showing periventricular white matter demyelination. (C) FLAIR coronal image, September 2018, shows a tumefactive left parietal lesion (arrow). (D) T2 axial image, September 2018, reflects multiple large active tumefactive lesions in periventricular and subcortical white matter. The arrow points to the same lesion indicated in (C). Case 2 35-year-old woman diagnosed with RRMS in 2015. The EDSS score was 1.5 at diagnosis. She started teriflunomide in May 2015. She suffered a first relapse in May 2016 (left ON) and a further two relapses in 2018 (right ON and facial palsy) treated with intravenous corticoids without sequelae. The EDSS score was 1.5. Due to clinical and radiological activity, it was decided to switch to Fingolimod. She stopped teriflunomide in May 2019 and the washout procedure was initiated. She needed two cholestyramine washouts until her blood level of teriflunomide was <0.02. In June 2019, eight weeks after stopping teriflunomide, the patient suffered a relapse with diplopia and dizziness, and her EDSS rose to 2.5. The MRI showed three new lesions, the largest in the left frontoparietal white matter, with central cavitation (Figure 2 [arrow]). The patient received 3 days of IV methylprednisolone with mild clinical improvement. Currently the patient is stable on Fingolimod.
Image 2 FLAIR coronal image (A) and T2 axial image (B,C), August 2018, showing periventricular white matter demyelination. (D) FLAIR coronal image, April 2019, shows a tumefactive left frontoparietal lesion with central cavitation (arrow). (E,F) T2 axial image, April 2019, shows multiple large active tumefactive lesions in periventricular and subcortical white matter. The arrow points to the same lesion indicated in (D). Discussion Relapse of MS may occur during the washout period of high efficacy DMT, however, it is unusual after discontinuing first-line DMT. We report two patients with RRMS who experienced a relapse after the accelerated elimination procedure (AEP) of teriflunomide and confirmation of negative plasmatic levels (<0.02µg/ml). It is known that teriflunomide has a complex mechanism of action that leads to immunosuppressive and antiinflammatory properties: it decreases the number of B and T activated lymphocytes, diminishes proinflammatory cytokines and can impede the formation of the immune synapse1. Additionally, in experimental allergic encephalomyelitis animal models, teriflunomide reduced demyelination and axonal loss and protected against oligodendrocyte cell death1. Teriflunomide is eliminated through direct biliary excretion of unchanged drug and undergoes enterohepatic circulation (ref). This results in an extremely slow elimination from plasma, which on average takes 6-8 months; but it can take up to 2 years to achieve systemic clearance of teriflunomide to negative plasma levels. The accelerated elimination process (AEP) with cholestyramine is thought to interrupt reabsorption of teriflunomide at the intestinal level, forming insoluble complexes which are sequestered in the small intestine and excreted in faeces4. According to the safety data sheet of teriflunomide, a washout period of 3.5 months (=5 half-lives of teriflunomide) or an AEP with cholestyramine results in a > 98% decrease of initial teriflunomide plasma concentration5. For women receiving teriflunomide who wish to become pregnant, the drug should be stopped and after AEP teriflunomide negative plasma levels must be verified by two separate tests at least 14 days apart5. In any situation of switching from teriflunomide to another DMT, it is not necessary to confirm the drug clearance after AEP. These cases highlight that MS relapse can be associated with the withdrawal of first line MS treatments. Time to relapse after cessation of teriflunomide in our cases (one and two months respectively) contrasts with data found
after reviewing literature3 (four months). This shorter time interval may be accounted for in this case by the washout period was not being accelerated with cholestyramine. We consider that the increased risk of complications from incomplete washout from teriflunomide needs to be balanced against the risk of relapse of MS. In cases of risk of MS activity, we should not wait for teriflunomide negative plasmatic levels confirmation before starting the next DMT.
Conflicts of interest: The authors declare no conflicts of interest Funding: No funding was provided This work complies with the standards of good clinical practice Submission declaration: We certify that this paper has not been published previously, is not under consideration for publication elsewhere, and that, if accepted, it will not be published elsewhere including electronically in the same form, in English or any other language, without the written consent of the copyright-holder. We take full responsibility for all information in the manuscript. We declare that all authors and contributors agree to the publication of this paper and to the conditions regarding publication as specified in the instructions for authors. If accepted for publication, I assign all rights to Multiple Sclerosis and Related Disorders
References 1. Scott LJ. Teriflunomide: A Review in Relapsing–Remitting Multiple Sclerosis. Drugs 2019;79(8):875-886 2. Harmel P, Schlunk F and Harms L. Fulminant rebound of relapsing–remitting multiple sclerosis after discontinuation of dimethyl fumarate: A case report. Mult Scler 2018;24(8):1131-1133 3. Yamout BI, Said M, Hannoun S, et al. Rebound syndrome after teriflunomide cessation in a patient with multiple sclerosis. J Neurol Sci. 2017;380:79-81 4. Robertson D, Dixon C, Aungst A, et al. Tolerability and efficacy of colestipol hydrochloride for accelerated elimination of teriflunomide. Expert Rev Clin Pharmacol. 2017;10:1403–1407. 5. Sanofi. Aubagio EMA summary of product characteristics, 2013.
Rebound after discontinuation of teriflunomide in patients with multiple sclerosis: 2 case reports ´ , R Lopez ´ A Fuerte-Hortigon Ru´ız , JD Guerra Hiraldo , ´ ´ ´ F Sanchez Fernandez , J Dotor Garc´ıa-Soto , L Paramo , ˜ , G Navarro-Mascarell , S Eichau JL Ruiz-Pena PII: DOI: Reference:
S2211-0348(20)30093-6 https://doi.org/10.1016/j.msard.2020.102017 MSARD 102017
To appear in:
Multiple Sclerosis and Related Disorders
Received date: Revised date: Accepted date:
3 January 2020 11 February 2020 21 February 2020
´ , ´ Please cite this article as: A Fuerte-Hortigon R Lopez Ru´ız , JD Guerra Hiraldo , ´ ´ ´ ˜ , G Navarro-Mascarell , F Sanchez Fernandez , J Dotor Garc´ıa-Soto , L Paramo , JL Ruiz-Pena S Eichau , Rebound after discontinuation of teriflunomide in patients with multiple sclerosis: 2 case reports, Multiple Sclerosis and Related Disorders (2020), doi: https://doi.org/10.1016/j.msard.2020.102017
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier B.V.
Highlights
Teriflunomide is an oral first-line therapy used in relapsing forms of MS
The washout period of teriflunomide may be accelerated by cholestyramine
Clearance of teriflunomide (<0.02µg/ml) are usually verified after washout period
Cases of MS relapse has been reported after the withdrawal of first-line therapies
Drug switching is possible after cholestyramine washout without level verification
Rebound after discontinuation of teriflunomide in patients with multiple sclerosis: 2 case reports Fuerte-Hortigón A1, López Ruíz R1, Guerra Hiraldo JD1, Sánchez Fernández F1, Dotor García-Soto J1, Páramo L1, RuizPeña JL1, Navarro-Mascarell G1, Eichau S1 1. Multiple Sclerosis Department. Virgen Macarena Hospital, Sevilla
Corresponding author: Alejandro Fuerte Hortigón. C/José Laguillo 29, 3rd portal, 4ºA [email protected] +34652524956 Conflicts of interest: The authors declare no conflicts of interest Funding: No funding has been received for this study.
Abstract: Teriflunomide is an oral first-line disease modifying treatment (DMT) for patients with relapsing-remitting multiple sclerosis (RRMS). It can take up to two years to achieve systemic clearance of teriflunomide to an acceptable level, but this washout period may be accelerated by administration of cholestyramine. Relapse of multiple sclerosis (MS) during washout of teriflunomide or other first-line DMT is not as common. We report two patients with RRMS who experienced a relapse after the accelerated elimination period (AEP) of teriflunomide and confirmation of negative plasmatic levels (<0.02µg/ml). In cases of risk of MS activity, we should not wait for teriflunomide negative plasmatic levels confirmation before starting the next DMT to reduce the risk of relapse. Keywords: Multiple Sclerosis, teriflunomide, accelerated elimination procedure, cholestyramine, tumefactive lesion Introduction Teriflunomide is an oral first-line disease modifying treatment (DMT) for patients with relapsing-remitting multiple sclerosis (RRMS). The main mechanism of action of teriflunomide is inhibition of the mitochondrial enzyme dihydroorotate-dehydrogenase (DHODH), precipitating a reduction of activated T and B lymphocytes1. It can take up to two years to achieve systemic clearance of teriflunomide to an acceptable level, but this washout period may be accelerated by administration of cholestyramine or activated charcoal for 11 days1. Relapse of multiple sclerosis (MS) is relatively common following cessation of high-efficacy disease modifying treatment (DMT) such as Natalizumab or Fingolimod, but relapses during washout of teriflunomide or other first-line DMT is not as common. However, recent cases of relapse of disease have been reported after the withdrawal of dimethyl fumarate2 and teriflunomide3. Here we describe two patients with MS relapse during the washout procedure of teriflunomide and after confirmation of plasma levels < 0.02 µg/ml. These patents showed worsening of disability and residual neurological sequelae despite steroid treatment.
Case 1 34-year-old male diagnosed with RRMS in 2001. Upon presentation, his expanded disability status scale (EDSS) estimate was 1.0. He was first treated with interferon-beta 1a (subcutaneous) 44 micrograms three times per week. Over the next 14 years, there was no clinical attack or MRI disease activity; however, in January 2017 it was decided to switch to teriflunomide due to injection-site erythema. He started teriflunomide in May 2017. After five months, the patient had developed left optic neuritis (ON). Visual acuity was 0.6 (corrected) and the EDSS score 1.5. He received treatment with corticoids with no improvement. In August 2018, teriflunomide was discontinued due to
persistent MRI activity in both 2017 and 2018. Washout procedure with cholestyramine was started at this time. During the washout period and after confirmation of teriflunomide plasma levels < 0.02 µg/ml (September 2018), the patient experienced a severe relapse with instability and right hemicorporal hypoesthesia and his EDSS score rose to 3. MRI showed four new, gadolinium-enhanced lesions, one of which was of a pseudotumoral character in the left parietal lobe (figure 1 [arrow]). The patient received methylprednisolone 1000 mg daily for 5 days without total clinical improvement.
Image 1 FLAIR coronal image (A) and T2 axial image (B), June 2018, showing periventricular white matter demyelination. (C) FLAIR coronal image, September 2018, shows a tumefactive left parietal lesion (arrow). (D) T2 axial image, September 2018, reflects multiple large active tumefactive lesions in periventricular and subcortical white matter. The arrow points to the same lesion indicated in (C). Case 2 35-year-old woman diagnosed with RRMS in 2015. The EDSS score was 1.5 at diagnosis. She started teriflunomide in May 2015. She suffered a first relapse in May 2016 (left ON) and a further two relapses in 2018 (right ON and facial palsy) treated with intravenous corticoids without sequelae. The EDSS score was 1.5. Due to clinical and radiological activity, it was decided to switch to Fingolimod. She stopped teriflunomide in May 2019 and the washout procedure was initiated. She needed two cholestyramine washouts until her blood level of teriflunomide was <0.02. In June 2019, eight weeks after stopping teriflunomide, the patient suffered a relapse with diplopia and dizziness, and her EDSS rose to 2.5. The MRI showed three new lesions, the largest in the left frontoparietal white matter, with central cavitation (Figure 2 [arrow]). The patient received 3 days of IV methylprednisolone with mild clinical improvement. Currently the patient is stable on Fingolimod.
Image 2 FLAIR coronal image (A) and T2 axial image (B,C), August 2018, showing periventricular white matter demyelination. (D) FLAIR coronal image, April 2019, shows a tumefactive left frontoparietal lesion with central cavitation (arrow). (E,F) T2 axial image, April 2019, shows multiple large active tumefactive lesions in periventricular and subcortical white matter. The arrow points to the same lesion indicated in (D). Discussion Relapse of MS may occur during the washout period of high efficacy DMT, however, it is unusual after discontinuing first-line DMT. We report two patients with RRMS who experienced a relapse after the accelerated elimination procedure (AEP) of teriflunomide and confirmation of negative plasmatic levels (<0.02µg/ml). It is known that teriflunomide has a complex mechanism of action that leads to immunosuppressive and antiinflammatory properties: it decreases the number of B and T activated lymphocytes, diminishes proinflammatory cytokines and can impede the formation of the immune synapse1. Additionally, in experimental allergic encephalomyelitis animal models, teriflunomide reduced demyelination and axonal loss and protected against oligodendrocyte cell death1. Teriflunomide is eliminated through direct biliary excretion of unchanged drug and undergoes enterohepatic circulation (ref). This results in an extremely slow elimination from plasma, which on average takes 6-8 months; but it can take up to 2 years to achieve systemic clearance of teriflunomide to negative plasma levels. The accelerated elimination process (AEP) with cholestyramine is thought to interrupt reabsorption of teriflunomide at the intestinal level, forming insoluble complexes which are sequestered in the small intestine and excreted in faeces4. According to the safety data sheet of teriflunomide, a washout period of 3.5 months (=5 half-lives of teriflunomide) or an AEP with cholestyramine results in a > 98% decrease of initial teriflunomide plasma concentration5. For women receiving teriflunomide who wish to become pregnant, the drug should be stopped and after AEP teriflunomide negative plasma levels must be verified by two separate tests at least 14 days apart5. In any situation of switching from teriflunomide to another DMT, it is not necessary to confirm the drug clearance after AEP. These cases highlight that MS relapse can be associated with the withdrawal of first line MS treatments. Time to relapse after cessation of teriflunomide in our cases (one and two months respectively) contrasts with data found
after reviewing literature3 (four months). This shorter time interval may be accounted for in this case by the washout period was not being accelerated with cholestyramine. We consider that the increased risk of complications from incomplete washout from teriflunomide needs to be balanced against the risk of relapse of MS. In cases of risk of MS activity, we should not wait for teriflunomide negative plasmatic levels confirmation before starting the next DMT.
Conflicts of interest: The authors declare no conflicts of interest Funding: No funding was provided This work complies with the standards of good clinical practice Submission declaration: We certify that this paper has not been published previously, is not under consideration for publication elsewhere, and that, if accepted, it will not be published elsewhere including electronically in the same form, in English or any other language, without the written consent of the copyright-holder. We take full responsibility for all information in the manuscript. We declare that all authors and contributors agree to the publication of this paper and to the conditions regarding publication as specified in the instructions for authors. If accepted for publication, I assign all rights to Multiple Sclerosis and Related Disorders
References 1. Scott LJ. Teriflunomide: A Review in Relapsing–Remitting Multiple Sclerosis. Drugs 2019;79(8):875-886 2. Harmel P, Schlunk F and Harms L. Fulminant rebound of relapsing–remitting multiple sclerosis after discontinuation of dimethyl fumarate: A case report. Mult Scler 2018;24(8):1131-1133 3. Yamout BI, Said M, Hannoun S, et al. Rebound syndrome after teriflunomide cessation in a patient with multiple sclerosis. J Neurol Sci. 2017;380:79-81 4. Robertson D, Dixon C, Aungst A, et al. Tolerability and efficacy of colestipol hydrochloride for accelerated elimination of teriflunomide. Expert Rev Clin Pharmacol. 2017;10:1403–1407. 5. Sanofi. Aubagio EMA summary of product characteristics, 2013.