Multiple Sclerosis and Related Disorders (2013) 2, 252–255
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
CASE REPORT
Rebound exacerbation multiple sclerosis following cessation of oral treatment Roy G. Berana,b,c,n, Yaser Hegazia, Raymond S. Schwartzd, Dennis J. Cordatoa,d a
Department of Neurology, Liverpool Hospital and The South Western Sydney Clinical School, University of New South Wales, New South Wales (NSW), Australia b School of Medicine, Griffith University, Queensland, Australia c Strategic Health Evaluators, PO Box 598, Northbridge, 1560 NSW, Australia d Southern Neurology, 2/19 Kensington Street, Kogarah, NSW, Australia Received 13 June 2012; received in revised form 4 October 2012; accepted 12 November 2012
KEYWORDS Multiple sclerosis; Fingolimod; BG12; Rebound
1.
Abstract Background: Multiple sclerosis (MS) management is changing, revolutionized by oral agents. Immune Reconstitution Inflammatory Syndrome (IRIS) describes exaggerated response to both exogenous (infective) and endogenous (non-infective) antigens. Methods: This paper reports two cases of MS ‘‘rebound’’ following withdrawal of oral treatments. Results: Two patients, with suboptimal response to interferons, trialled oral MS treatment (fingolimod and BG12) with excellent response. Upon cessation both experienced MS ‘‘rebound’’ which responded to steroids. Conclusions: ‘‘Rebound’’ may occur following withdrawal of oral MS therapies. Patients should be advised accordingly and possibly started on alternative treatment before the immunomodulating effect of therapy has subsided. & 2013 Published by Elsevier B.V.
Introduction
Management of multiple sclerosis (MS) has been revolutionized with new oral immunomodulating agents, including fingolimod recently approved in the United States of
n Corresponding author at:Strategic Health Evaluators, PO Box 598, Northbridge, 1560 NSW, Australia. Tel.: +61 2 9828 3646; fax: +61 2 9828 3648. E-mail address: [email protected] (R.G. Beran).
2211-0348/$ - see front matter & 2013 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.msard.2012.11.001
America, Europe and Australia and BG12 having completed phase III trials (Kappos et al., 2010; Mehling et al., 2011; Linker et al., 2011). Fingolimod, an oral sphingosine -1-phosphate (S1P) receptor modulator, binds with high binding affinity to G-protein-coupled receptors, specific for S1P. S1P is internalised and rendered ineffective, thereby trapping naive and central memory T-cells within lymphoid tissue (Mehling et al., 2011). BG-12, an oral fumarate derivative, is an immunomodulatory agent with an unknown mode of action, thought to have neuroprotective and anti-inflammatory properties (Linker
Rebound exacerbation MS
253
Fig. 1 (a) T2-fluid attenuated inversion recovery (FLAIR) axial image of case 1, whilst on interferon beta 1a, from March 2007 demonstrating numerous cerebral demyelinating lesions, without significant oedema; (b) post-gadolinium T1 image from March 2007 demonstrating peripheral gadolinium enhancement of a left frontal white matter lesion; (c) T2-FLAIR image of case 1, whilst on fingolimod, from April 2008 demonstrating mild reduction in background demyelination and (d) post-gadolinium T2-fluid attenuated inversion recovery (FLAIR) axial image, post-cessation of fingolimod, from November 2008, demonstrating the presence of numerous gadolinium enhancing lesions on a background of extensive and confluent white matter disease.
et al., 2011). In vitro studies indicate activation of the transcription factor nuclear-factor-(erythroid-derived 2)-related factor 2 (Nrf2), thought to contribute to the maintenance of myelin, and induction of expression of endogenous antioxidative factors (Linker et al., 2011). Immune Reconstitution Inflammatory Syndrome (IRIS) was first described with infections, such as HIV/AIDS and more recently with natalizumab-associated progressive multifocal leukoencephalopathy in conjunction with JC virus (Wenning et al., 2009). This suggested that IRIS was caused by an exogenous agent. More recently, the term ‘IRIS’ has been used to describe the rebound phenomenon encountered after interruption of natalizumab treatment in which there is an acute exacerbation of MS, suggesting an endogenous antigenic cause without infection. Use of the term IRIS, for an exaggerated immune response following discontinuation of MS therapy, raises questions whether ‘‘IRIS’’ equates to rebound. O0 Connor et al. favoured ‘‘rebound’’ (worsening of disease activity beyond pre-treatment levels) and ‘‘disease activity return’’ in their post-hoc analysis of patients following discontinuation of natalizumab (O’Connor et al., 2011) They identified a
consistent return of disease activity in an analysis of 1866 patients but not beyond that found in placebo-treated levels from clinical studies and concluded absence of a ‘‘rebound’’ phenomenon. Miravalle et al. found 38% of their 32 patients had severe relapses and unusually extensive MRI activity following withdrawal of natalizumab, including 3 cases of CSF pleocytosis, supporting presence of ‘‘rebound’’ (Miravalle et al. 2011). Differences in methodology may contribute to the conflicting results. This paper reports two cases of acute uncharacteristic severe exacerbations of MS following withdrawal of new oral MS treatments. The authors believe this to be the first report of a rebound phenomenon, following cessation of new oral agents.
2. 2.1.
Methods Case report 1
A 31 year old female with a three year history of MS, initially manifesting with left optic neuritis and left
254
R.G Beran et al. medullaris. The patient improved after treatment with 1 g intravenous methylprednisolone daily for five days.
3.
Fig. 2 T2-FLAIR sagittal image of case 2 demonstrating an elongated segment of high signal change within the cervical cord.
hemiparesis was treated with interferon beta 1b (Betaferon) and interferon beta 1a (Avonex) before randomization into the MS TRANSFORM trial. She had evidence of disease activity whilst on the interferon therapy, including attacks of optic neuritis and paraesthesia, in the 12 months prior to randomization. In 2008, prior to entering the extension study, she decided to start a family and in consultation her immunomodulating therapy was discontinued. Five weeks after treatment cessation, she developed a gradual recurrence of MS symptoms evolving into a severe exacerbation with ataxia, nystagmus, progressive quadraparesis, including generalised grade 3/5 pyramidal weakness and a sensory level to the upper chest. An MRI of brain and spine demonstrated significant increase in MS activity involving the cerebrum (Fig. 1), cerebellum and the cervical cord. She was later confirmed to have been randomized to fingolimod 1.25 mg. The patient improved after treatment with intravenous methylprednisolone 1 g daily for 5 days.
2.2.
Discussion
These two cases presented with characteristic relapsing remitting MS satisfying inclusion and exclusion criteria for clinical trials of new MS treatments (Kappos et al., 2010). Both had clinical and MRI evidence of disease activity whilst on beta-interferon therapy but neither had particularly aggressive clinical disease and both were well controlled within their respective trials. They chose to stop treatment because they wished to start a family and avoid potential teratogenicity. These patients experienced significant and, for them, uncharacteristically severe exacerbations of MS (Figs. 1 and 2). The severity of exacerbation is consistent with the ‘‘rebound’’ phenomenon. Many patients with MS are of reproductive age and may elect to discontinue effective treatment for fear of teratogenesis. These cases emphasize the need to inform such patients of the possibility of an exaggerated relapse, akin to ‘‘rebound’’, (as a component of duty of care), once the immunomodulating effect of therapy has subsided. Publication of data, from existing trials of oral agents, may be of value to examine further this phenomenon. The washout periods for fingolimod and BG12 are two months and one month, respectively (Mehling et al., 2011; Linker et al., 2011). Due to the limited long-term experience with oral treatments for MS, the risk for a ‘‘rebound’’ exacerbation of disease, after treatment withdrawal, is unknown but these cases demonstrate its potential. Expression of such aggressive relapse may occur within one to two months of treatment cessation, without ability to define susceptible patients. Having demonstrated the possibility of ‘‘rebound’’, following cessation of new oral therapies, it may be prudent to consider initiating alternative treatment to compensate for elimination of the immunomodulating activity when effective treatment is withdrawn. Whilst both patients responded well to interval steroid therapy for their acute MS exacerbations, these case reports highlight the need to be aware of the potential for ‘‘rebound’’ or exaggerated return of disease activity and to inform patients accordingly.
Case report 2
Conflict of interest A 34 year old male presented in 2001, aged 23 years, with asymmetric right4left optic neuritis and lower limb dysesthesia due to MS. He was commenced on interferon beta 1b (Betaferon) which was poorly tolerated. In 2007 he experienced a relapse with lower limb weakness that responded to intravenous methylprednisolone. He was subsequently randomized into the BG12 DEFINE trial and continued into the open label oral extension phase. In March 2010, he decided to plan a family and after consultation he discontinued BG12 to minimise potential teratogenicity. In October 2010, he complained of midthoracic pain, gait imbalance and urgency of micturition. His walking distance significantly reduced to less than one kilometre. An MRI spine identified new large elongated plaques 10 cm long in the cervical spine (Fig. 2) and 9.5 cm long in the midthoracic cord as well as scattered plaques in the conus
All authors have no conflict of interest to declare and there has been no funding involved in these case report.
Acknowledgements The authors wish to acknowledge the assistance of Dr. Jeffrey Kuan, neuroradiologist, who reviewed MRI scans of Case 1.
References Kappos L, Radue EW, O’Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. New England Journal of Medicine 2010;362:387–401.
Rebound exacerbation MS Linker RA, Lee DH, Ryan S, et al. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 2011;134(3):678–92. Mehling M, Johnson TA, Antel J, Kappos L, Bar-Or A. Clinical immunology of the sphingosine 1-phosphate receptor modulator fingolimod (FTY720) in multiple sclerosis. Neurology 2011;76(Suppl. 3):S20–7. O’Connor PW, Goodman A, Kappos L, et al. Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. Neurology 2011;76:1858–65.
255 Miravalle A, Jensen R, Kinkel P. Immune reconstitution inflammatory syndrome in patients with multiple sclerosis following cessation of natalizumab therapy. Archives of Neurology 2011;68: 186–91. Wenning W, Haghikia A, Laubenberger J, et al. Treatment of progressive multifocal leukoencephalopathy associated with natalizumab. New England Journal of Medicine 2009;361: 1075–80.
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
CASE REPORT
Rebound exacerbation multiple sclerosis following cessation of oral treatment Roy G. Berana,b,c,n, Yaser Hegazia, Raymond S. Schwartzd, Dennis J. Cordatoa,d a
Department of Neurology, Liverpool Hospital and The South Western Sydney Clinical School, University of New South Wales, New South Wales (NSW), Australia b School of Medicine, Griffith University, Queensland, Australia c Strategic Health Evaluators, PO Box 598, Northbridge, 1560 NSW, Australia d Southern Neurology, 2/19 Kensington Street, Kogarah, NSW, Australia Received 13 June 2012; received in revised form 4 October 2012; accepted 12 November 2012
KEYWORDS Multiple sclerosis; Fingolimod; BG12; Rebound
1.
Abstract Background: Multiple sclerosis (MS) management is changing, revolutionized by oral agents. Immune Reconstitution Inflammatory Syndrome (IRIS) describes exaggerated response to both exogenous (infective) and endogenous (non-infective) antigens. Methods: This paper reports two cases of MS ‘‘rebound’’ following withdrawal of oral treatments. Results: Two patients, with suboptimal response to interferons, trialled oral MS treatment (fingolimod and BG12) with excellent response. Upon cessation both experienced MS ‘‘rebound’’ which responded to steroids. Conclusions: ‘‘Rebound’’ may occur following withdrawal of oral MS therapies. Patients should be advised accordingly and possibly started on alternative treatment before the immunomodulating effect of therapy has subsided. & 2013 Published by Elsevier B.V.
Introduction
Management of multiple sclerosis (MS) has been revolutionized with new oral immunomodulating agents, including fingolimod recently approved in the United States of
n Corresponding author at:Strategic Health Evaluators, PO Box 598, Northbridge, 1560 NSW, Australia. Tel.: +61 2 9828 3646; fax: +61 2 9828 3648. E-mail address: [email protected] (R.G. Beran).
2211-0348/$ - see front matter & 2013 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.msard.2012.11.001
America, Europe and Australia and BG12 having completed phase III trials (Kappos et al., 2010; Mehling et al., 2011; Linker et al., 2011). Fingolimod, an oral sphingosine -1-phosphate (S1P) receptor modulator, binds with high binding affinity to G-protein-coupled receptors, specific for S1P. S1P is internalised and rendered ineffective, thereby trapping naive and central memory T-cells within lymphoid tissue (Mehling et al., 2011). BG-12, an oral fumarate derivative, is an immunomodulatory agent with an unknown mode of action, thought to have neuroprotective and anti-inflammatory properties (Linker
Rebound exacerbation MS
253
Fig. 1 (a) T2-fluid attenuated inversion recovery (FLAIR) axial image of case 1, whilst on interferon beta 1a, from March 2007 demonstrating numerous cerebral demyelinating lesions, without significant oedema; (b) post-gadolinium T1 image from March 2007 demonstrating peripheral gadolinium enhancement of a left frontal white matter lesion; (c) T2-FLAIR image of case 1, whilst on fingolimod, from April 2008 demonstrating mild reduction in background demyelination and (d) post-gadolinium T2-fluid attenuated inversion recovery (FLAIR) axial image, post-cessation of fingolimod, from November 2008, demonstrating the presence of numerous gadolinium enhancing lesions on a background of extensive and confluent white matter disease.
et al., 2011). In vitro studies indicate activation of the transcription factor nuclear-factor-(erythroid-derived 2)-related factor 2 (Nrf2), thought to contribute to the maintenance of myelin, and induction of expression of endogenous antioxidative factors (Linker et al., 2011). Immune Reconstitution Inflammatory Syndrome (IRIS) was first described with infections, such as HIV/AIDS and more recently with natalizumab-associated progressive multifocal leukoencephalopathy in conjunction with JC virus (Wenning et al., 2009). This suggested that IRIS was caused by an exogenous agent. More recently, the term ‘IRIS’ has been used to describe the rebound phenomenon encountered after interruption of natalizumab treatment in which there is an acute exacerbation of MS, suggesting an endogenous antigenic cause without infection. Use of the term IRIS, for an exaggerated immune response following discontinuation of MS therapy, raises questions whether ‘‘IRIS’’ equates to rebound. O0 Connor et al. favoured ‘‘rebound’’ (worsening of disease activity beyond pre-treatment levels) and ‘‘disease activity return’’ in their post-hoc analysis of patients following discontinuation of natalizumab (O’Connor et al., 2011) They identified a
consistent return of disease activity in an analysis of 1866 patients but not beyond that found in placebo-treated levels from clinical studies and concluded absence of a ‘‘rebound’’ phenomenon. Miravalle et al. found 38% of their 32 patients had severe relapses and unusually extensive MRI activity following withdrawal of natalizumab, including 3 cases of CSF pleocytosis, supporting presence of ‘‘rebound’’ (Miravalle et al. 2011). Differences in methodology may contribute to the conflicting results. This paper reports two cases of acute uncharacteristic severe exacerbations of MS following withdrawal of new oral MS treatments. The authors believe this to be the first report of a rebound phenomenon, following cessation of new oral agents.
2. 2.1.
Methods Case report 1
A 31 year old female with a three year history of MS, initially manifesting with left optic neuritis and left
254
R.G Beran et al. medullaris. The patient improved after treatment with 1 g intravenous methylprednisolone daily for five days.
3.
Fig. 2 T2-FLAIR sagittal image of case 2 demonstrating an elongated segment of high signal change within the cervical cord.
hemiparesis was treated with interferon beta 1b (Betaferon) and interferon beta 1a (Avonex) before randomization into the MS TRANSFORM trial. She had evidence of disease activity whilst on the interferon therapy, including attacks of optic neuritis and paraesthesia, in the 12 months prior to randomization. In 2008, prior to entering the extension study, she decided to start a family and in consultation her immunomodulating therapy was discontinued. Five weeks after treatment cessation, she developed a gradual recurrence of MS symptoms evolving into a severe exacerbation with ataxia, nystagmus, progressive quadraparesis, including generalised grade 3/5 pyramidal weakness and a sensory level to the upper chest. An MRI of brain and spine demonstrated significant increase in MS activity involving the cerebrum (Fig. 1), cerebellum and the cervical cord. She was later confirmed to have been randomized to fingolimod 1.25 mg. The patient improved after treatment with intravenous methylprednisolone 1 g daily for 5 days.
2.2.
Discussion
These two cases presented with characteristic relapsing remitting MS satisfying inclusion and exclusion criteria for clinical trials of new MS treatments (Kappos et al., 2010). Both had clinical and MRI evidence of disease activity whilst on beta-interferon therapy but neither had particularly aggressive clinical disease and both were well controlled within their respective trials. They chose to stop treatment because they wished to start a family and avoid potential teratogenicity. These patients experienced significant and, for them, uncharacteristically severe exacerbations of MS (Figs. 1 and 2). The severity of exacerbation is consistent with the ‘‘rebound’’ phenomenon. Many patients with MS are of reproductive age and may elect to discontinue effective treatment for fear of teratogenesis. These cases emphasize the need to inform such patients of the possibility of an exaggerated relapse, akin to ‘‘rebound’’, (as a component of duty of care), once the immunomodulating effect of therapy has subsided. Publication of data, from existing trials of oral agents, may be of value to examine further this phenomenon. The washout periods for fingolimod and BG12 are two months and one month, respectively (Mehling et al., 2011; Linker et al., 2011). Due to the limited long-term experience with oral treatments for MS, the risk for a ‘‘rebound’’ exacerbation of disease, after treatment withdrawal, is unknown but these cases demonstrate its potential. Expression of such aggressive relapse may occur within one to two months of treatment cessation, without ability to define susceptible patients. Having demonstrated the possibility of ‘‘rebound’’, following cessation of new oral therapies, it may be prudent to consider initiating alternative treatment to compensate for elimination of the immunomodulating activity when effective treatment is withdrawn. Whilst both patients responded well to interval steroid therapy for their acute MS exacerbations, these case reports highlight the need to be aware of the potential for ‘‘rebound’’ or exaggerated return of disease activity and to inform patients accordingly.
Case report 2
Conflict of interest A 34 year old male presented in 2001, aged 23 years, with asymmetric right4left optic neuritis and lower limb dysesthesia due to MS. He was commenced on interferon beta 1b (Betaferon) which was poorly tolerated. In 2007 he experienced a relapse with lower limb weakness that responded to intravenous methylprednisolone. He was subsequently randomized into the BG12 DEFINE trial and continued into the open label oral extension phase. In March 2010, he decided to plan a family and after consultation he discontinued BG12 to minimise potential teratogenicity. In October 2010, he complained of midthoracic pain, gait imbalance and urgency of micturition. His walking distance significantly reduced to less than one kilometre. An MRI spine identified new large elongated plaques 10 cm long in the cervical spine (Fig. 2) and 9.5 cm long in the midthoracic cord as well as scattered plaques in the conus
All authors have no conflict of interest to declare and there has been no funding involved in these case report.
Acknowledgements The authors wish to acknowledge the assistance of Dr. Jeffrey Kuan, neuroradiologist, who reviewed MRI scans of Case 1.
References Kappos L, Radue EW, O’Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. New England Journal of Medicine 2010;362:387–401.
Rebound exacerbation MS Linker RA, Lee DH, Ryan S, et al. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 2011;134(3):678–92. Mehling M, Johnson TA, Antel J, Kappos L, Bar-Or A. Clinical immunology of the sphingosine 1-phosphate receptor modulator fingolimod (FTY720) in multiple sclerosis. Neurology 2011;76(Suppl. 3):S20–7. O’Connor PW, Goodman A, Kappos L, et al. Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. Neurology 2011;76:1858–65.
255 Miravalle A, Jensen R, Kinkel P. Immune reconstitution inflammatory syndrome in patients with multiple sclerosis following cessation of natalizumab therapy. Archives of Neurology 2011;68: 186–91. Wenning W, Haghikia A, Laubenberger J, et al. Treatment of progressive multifocal leukoencephalopathy associated with natalizumab. New England Journal of Medicine 2009;361: 1075–80.
