Review Article
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Treatment of Pediatric Multiple Sclerosis Barbara Kornek1 1 Department of Neurology, Medical University of Vienna,
Vienna, Austria
Address for correspondence Barbara Kornek, MD, Department of Neurology, Medical University of Vienna, Waehringer Guertel 18-20, A–1090 Vienna, Austria (e-mail: [email protected]).
Neuropediatrics 2013;44:309–313.
Keywords
► multiple sclerosis ► pediatric ► disease-modifying therapy
Multiple sclerosis (MS) in children and adolescents has received increased attention during the past decade. Although not tested in randomized placebo-controlled trials, first-line disease-modifying therapies are widely used in patients with MS who are younger than 18 years. This review summarizes current treatment practices, possible future treatment options, and gives insight into special problems in the treatment of pediatric patients with MS.
Introduction
Treatment of Acute MS Attacks
In 3 to 5% of cases, multiple sclerosis (MS) manifests before the age of 18 years.1–4 Although the pathogenesis of the disease does not differ between the age-groups, several particularities of the young patients, relevant for patient care, require attention. During childhood, there is an even gender ratio, and only after puberty, a female preponderance is seen.5 The disease course is usually relapsing-remitting, whereas primary progressive MS is extremely rare in the pediatric population with MS.1,3 Recovery from relapse-related symptoms seem to be more rapid6; however, pediatric patients with MS show a higher relapse rate than adults.7 With respect to long-term prognosis, patients with pediatric-onset MS may reach milestones of disability 10 years earlier than their adult counterparts.2,3 Relevant cognitive impairment has been found up to 35% of pediatric patients with MS8 and some patients continue to develop cognitive deficits on follow-up.9 Therefore, although in the early phase of the disease, accumulation of disability occurs slower, and the long-term outcome of the disease remains doubtful, underscoring the need for further investigation in this age-group. Several recent reviews have provided detailed information on the use of disease-modifying therapy in the pediatric MS population.10–17 The aim of this review is to summarize current and emerging treatment options as well as to discuss the management of children with MS.
Steroid therapy accelerates recovery from relapse-related symptoms,18 but long-term effects on disease evolution have not been demonstrated yet.19,20 High-dose intravenous methylprednisolone given during 3 to 5 days is generally accepted as the first choice for the treatment of acute attacks.10–13 There is consensus that acute attacks do not always require treatment, depending on the severity of the attack.21 Oral steroid tapers were considered, but not automatically used.21 In patients with severe attack and/or incomplete recovery, a second steroid pulse can be offered.10,13 Plasma exchange is a treatment option for steroid-refractory relapses in adults.22 There is only limited data available on its use on children23; however, in case of severe relapse-rated impairment, plasma exchange should be considered.
received August 20, 2013 accepted after revision September 29, 2013 published online November 7, 2013
Issue Theme Neuroinflammation Update: New Insights and Future Directions; Guest Editor, Kevin Rostasy, MD.
First-Line Therapy Three interferon beta preparations and glatiramer acetate are available for adults with active relapsing-remitting multiple sclerosis (RRMS), showing a 29 to 34% reduction in the relapse rate as well as a reduction of new and contrast-enhancing lesions on magnetic resonance imaging (MRI) compared with placebo.24–27 In adult patients, the time to a second, diseasedefining attack was significantly delayed after a clinically isolated syndrome (CIS).28–31 In contrast, the impact of firstline disease-modifying therapy on disability progression is modest32 and clinical effects beyond 2 years are uncertain, a relevant point to consider for a disease of 40 to 50 years duration. However, long-term follow-up studies indicate that
© 2013 Georg Thieme Verlag KG Stuttgart · New York
DOI http://dx.doi.org/ 10.1055/s-0033-1359308. ISSN 0174-304X.
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Abstract
Treatment in Childhood MS
Kornek
early treatment initiation and a longer duration on diseasemodifying therapy may delay the time to secondary progression, reduce the risk of reaching milestones of disability,33–36 and may also reduce MS-related causes of mortality.37 No randomized controlled trials have been performed on children and adolescents with MS. Limited experience in the pediatric population indicate that the use of interferon beta and glatiramer acetate is safe and well tolerated.38–47 On the basis of the experience with adults as well as of the available data on children, the International Pediatric MS Study Group (IPMSSG), therefore, recommends that all children and adolescents with a diagnosis of MS according to the consensus criteria48,49 should be considered for treatment with a first-line disease-modifying agent.15 Pediatric CIS patients, with typical clinical and MRI features, who do not yet fulfill the McDonald criteria for both dissemination in space and dissemination in time50 may also benefit from prompt initiation of therapy.15 Side effects of β-interferons in children are comparable to those in adults and include injection-site reactions, flu-like symptoms, and laboratory abnormalities, such as leukopenia, thrombocytopenia, anemia, and transient elevation of liver enzymes.38–46 In children younger than 10 years, treated with interferon β-1b, elevation in transaminases occurred more often compared with patients above the age of 10 years.43 Laboratory abnormalities however are usually graded as mild and do not lead to treatment discontinuation. There are no recommendations available regarding dosing schedules in pediatric MS; however, most patients older than 10 years were escalated to full dose. In pediatric patients treated with glatiramer acetate, no new or unexpected side effects were observed. Small retrospective studies reported injection site reactions and transient systemic reactions, which resolved without sequelae.41,47
Second-Line Therapy Despite compliant first-line therapy, some MS patients continue to experience clinical and MRI activity in terms of relapses, accumulation of disability, and the occurrence of new and contrast-enhancing lesions on MRI.51 The working definition for inadequate treatment response in children, proposed by the IPMSSG includes a minimum time on fulldose therapy for 6 months, and increase or no reduction in relapse rate, or new and contrast-enhancing lesions on MRI or two or more confirmed relapses within a 12-month period or less.15 In a retrospective study of 258 pediatric MS patients, approximately 28% of patients switched to another agent during a 3-year period because of refractory disease. Natalizumab, approved for patients aged 18 years or older appears to be the most effective agent currently available for treatment of patients with active RRMS.32 Compared with placebo, it shows a 68% reduction of relapse rate and probably may decrease the risk of disability progression.52,53 Natalizumab has been also used in adolescents with MS.54–58 The largest series published so far included 55 pediatric MS patients, of whom only 3 patients experienced a relapse during the treatment period.57 In another series, disease activity returned within 6 months following treatment cessation in six of eight patients.58 Neuropediatrics
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The use of natalizumab is limited by the risk of progressive multifocal leukoencephalopathy (PML) occurring in more than 2:1,000 patients.59 Assessment of the John Cunningham virusantibody status may help for risk stratification in patients treated with natalizumab.60–62 Children and adolescents have lower JC virus infection rates than adults,63 but data regarding the JC antibody status in children as determined by the currently used Stratify test (STRATIFY JCV, Biogen Idec, Weston, Massachusetts, United States) are limited.57 Fingolimod, the first approved oral agent for the treatment of MS, has shown to reduce relapse activity by 54% compared with placebo and has a profound effect on MR activity.64,65 It was approved in Europe in 2010 for adults with active RRMS. Fingolimod binds to the sphingosine-1-phosphate receptor on lymphocytes, preventing lymphocyte egress from lymph nodes. This results in a profound decrease in the number of peripherally circulating lymphocytes and therefore prevents autoaggressive lymphocytes from entering into the brain. Two patients developed severe varicella-zoster exacerbation, suggesting that fingolimod may have significant immunosuppressive effects.66 Furthermore, fingolimod induces a transient decrease of the heart rate after first dose administration. As in the postmarketing surveillance, two unexplained deaths during sleep occurred, in which a relation to fingolimod could not be ruled out, the Food and Drug Administration and European Medicines Agency announced new contraindication for its use in patients with certain cardiac conditions.67 Because of these safety concerns, the use of fingolimod should be undertaken after a serious riskbenefit evaluation.66 There is no information regarding safety, tolerability, and efficacy available in children yet. However, it is very likely that fingolimod will be of growing importance in the near future as seen in adult MS. Cyclophosphamide, although used for a long time is not approved for the treatment of MS. In a retrospective survey of 17 children, the relapse rate as well as disability as measured by the EDSS improved within the year following treatment initiation.68 However, patients under treatment with cyclophosphamide are exposed to an increased risk of infections, amenorrhea, bladder cancer, and secondary malignancies. Furthermore, immunosuppressive treatment may limit a subsequent use of natalizumab, since prior use of immunosuppression is a risk factor for the development of PML.60 Mitoxantrone, which is approved in adults with highly active MS69 has been applied in four pediatric MS patients so far.70 However, its use is not recommended in children because of its cardiotoxicity and the risk of secondary leukaemia.15
Emerging Therapies Several new oral agents as well as monoclonal antibodies have been developed and for some of them, approval is awaited shortly. However, none of these agents is currently being tested in pediatric MS. Dimethyl fumarate, the active compound of BG-12, which may enhance the cellular response against oxidative stress, demonstrated a 50% reduction of relapse rates compared with placebo paralleled by a reduction of new lesion formation on
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MRI.71,72 Flushing and gastrointestinal symptoms such as nausea, abdominal pain, and diarrhea were the most common reported side effects during the first months of treatment.71,72 Two cases of PML occurring during fumaric acid ester treatment in patients with psoriasis were recently described.73,74 However, there have been no cases of PML reported in the context of RRMS treated with dimethyl fumarate. Teriflunomide, which reduces the activity of proliferating T and B lymphocytes, therefore, diminishing the inflammatory response to autoantigens, decreased the annualized relapse rate for 31% compared with placebo.75,76 It has been well tolerated in adults, although elevation of transaminases and alopecia occurred. However, risk of teratogenicity may caution its use in women of childbearing age.66 Laquinimod, which may exhibit both immunomodulatory and neuroprotective properties, has a moderate efficacy in reducing relapse rate, but it may have a more pronounced effect in reducing sustained disability progression and brain atrophy.77,78 Rituximab has shown efficacy in phase II trials in adults79; however, more than 50 cases of PML have been reported.80 Reduction in relapse rate has been also reported in a pediatric MS patient.81 Alemtuzumab, a humanized monoclonal antibody targeting CD52, has demonstrated a clear superiority against subcutaneous interferon β-1a in term of relapse and MR activity.82,83 However, infusion-related reactions, secondary autoimmunity, and infection require enhanced-treatment monitoring. Daclizumab, a humanized monoclonal antibody specific for the interleukin 2-receptor α chain, has been tested in phase II trials in adult MS,84,85 whereas the results of the phase III trial are awaited. It has been shown to be only partially effective in seven pediatric MS patients with breakthrough disease.86
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Management of Pediatric MS Patients 16
Limited efficacy, side effects, intramuscular, or subcutaneous application, as well as the need of treatment continuation even in periods of stable disease may influence treatment adherence. Adherence to injectable therapies in adult MS has been shown to range between 60 and 80%.87 A recent survey on 258 pediatric patients found that 16% of the patients discontinued therapy because of side effects or reduced compliance after a mean treatment period of 1.1 years.51 The high frequency of change of therapy because of breakthrough disease, nontolerance or poor compliance, as well as missing long-term safety data of first-line and second-line agents underline the need for controlled trials in pediatric patients with MS.
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Treatment of Pediatric Multiple Sclerosis Barbara Kornek1 1 Department of Neurology, Medical University of Vienna,
Vienna, Austria
Address for correspondence Barbara Kornek, MD, Department of Neurology, Medical University of Vienna, Waehringer Guertel 18-20, A–1090 Vienna, Austria (e-mail: [email protected]).
Neuropediatrics 2013;44:309–313.
Keywords
► multiple sclerosis ► pediatric ► disease-modifying therapy
Multiple sclerosis (MS) in children and adolescents has received increased attention during the past decade. Although not tested in randomized placebo-controlled trials, first-line disease-modifying therapies are widely used in patients with MS who are younger than 18 years. This review summarizes current treatment practices, possible future treatment options, and gives insight into special problems in the treatment of pediatric patients with MS.
Introduction
Treatment of Acute MS Attacks
In 3 to 5% of cases, multiple sclerosis (MS) manifests before the age of 18 years.1–4 Although the pathogenesis of the disease does not differ between the age-groups, several particularities of the young patients, relevant for patient care, require attention. During childhood, there is an even gender ratio, and only after puberty, a female preponderance is seen.5 The disease course is usually relapsing-remitting, whereas primary progressive MS is extremely rare in the pediatric population with MS.1,3 Recovery from relapse-related symptoms seem to be more rapid6; however, pediatric patients with MS show a higher relapse rate than adults.7 With respect to long-term prognosis, patients with pediatric-onset MS may reach milestones of disability 10 years earlier than their adult counterparts.2,3 Relevant cognitive impairment has been found up to 35% of pediatric patients with MS8 and some patients continue to develop cognitive deficits on follow-up.9 Therefore, although in the early phase of the disease, accumulation of disability occurs slower, and the long-term outcome of the disease remains doubtful, underscoring the need for further investigation in this age-group. Several recent reviews have provided detailed information on the use of disease-modifying therapy in the pediatric MS population.10–17 The aim of this review is to summarize current and emerging treatment options as well as to discuss the management of children with MS.
Steroid therapy accelerates recovery from relapse-related symptoms,18 but long-term effects on disease evolution have not been demonstrated yet.19,20 High-dose intravenous methylprednisolone given during 3 to 5 days is generally accepted as the first choice for the treatment of acute attacks.10–13 There is consensus that acute attacks do not always require treatment, depending on the severity of the attack.21 Oral steroid tapers were considered, but not automatically used.21 In patients with severe attack and/or incomplete recovery, a second steroid pulse can be offered.10,13 Plasma exchange is a treatment option for steroid-refractory relapses in adults.22 There is only limited data available on its use on children23; however, in case of severe relapse-rated impairment, plasma exchange should be considered.
received August 20, 2013 accepted after revision September 29, 2013 published online November 7, 2013
Issue Theme Neuroinflammation Update: New Insights and Future Directions; Guest Editor, Kevin Rostasy, MD.
First-Line Therapy Three interferon beta preparations and glatiramer acetate are available for adults with active relapsing-remitting multiple sclerosis (RRMS), showing a 29 to 34% reduction in the relapse rate as well as a reduction of new and contrast-enhancing lesions on magnetic resonance imaging (MRI) compared with placebo.24–27 In adult patients, the time to a second, diseasedefining attack was significantly delayed after a clinically isolated syndrome (CIS).28–31 In contrast, the impact of firstline disease-modifying therapy on disability progression is modest32 and clinical effects beyond 2 years are uncertain, a relevant point to consider for a disease of 40 to 50 years duration. However, long-term follow-up studies indicate that
© 2013 Georg Thieme Verlag KG Stuttgart · New York
DOI http://dx.doi.org/ 10.1055/s-0033-1359308. ISSN 0174-304X.
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Abstract
Treatment in Childhood MS
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early treatment initiation and a longer duration on diseasemodifying therapy may delay the time to secondary progression, reduce the risk of reaching milestones of disability,33–36 and may also reduce MS-related causes of mortality.37 No randomized controlled trials have been performed on children and adolescents with MS. Limited experience in the pediatric population indicate that the use of interferon beta and glatiramer acetate is safe and well tolerated.38–47 On the basis of the experience with adults as well as of the available data on children, the International Pediatric MS Study Group (IPMSSG), therefore, recommends that all children and adolescents with a diagnosis of MS according to the consensus criteria48,49 should be considered for treatment with a first-line disease-modifying agent.15 Pediatric CIS patients, with typical clinical and MRI features, who do not yet fulfill the McDonald criteria for both dissemination in space and dissemination in time50 may also benefit from prompt initiation of therapy.15 Side effects of β-interferons in children are comparable to those in adults and include injection-site reactions, flu-like symptoms, and laboratory abnormalities, such as leukopenia, thrombocytopenia, anemia, and transient elevation of liver enzymes.38–46 In children younger than 10 years, treated with interferon β-1b, elevation in transaminases occurred more often compared with patients above the age of 10 years.43 Laboratory abnormalities however are usually graded as mild and do not lead to treatment discontinuation. There are no recommendations available regarding dosing schedules in pediatric MS; however, most patients older than 10 years were escalated to full dose. In pediatric patients treated with glatiramer acetate, no new or unexpected side effects were observed. Small retrospective studies reported injection site reactions and transient systemic reactions, which resolved without sequelae.41,47
Second-Line Therapy Despite compliant first-line therapy, some MS patients continue to experience clinical and MRI activity in terms of relapses, accumulation of disability, and the occurrence of new and contrast-enhancing lesions on MRI.51 The working definition for inadequate treatment response in children, proposed by the IPMSSG includes a minimum time on fulldose therapy for 6 months, and increase or no reduction in relapse rate, or new and contrast-enhancing lesions on MRI or two or more confirmed relapses within a 12-month period or less.15 In a retrospective study of 258 pediatric MS patients, approximately 28% of patients switched to another agent during a 3-year period because of refractory disease. Natalizumab, approved for patients aged 18 years or older appears to be the most effective agent currently available for treatment of patients with active RRMS.32 Compared with placebo, it shows a 68% reduction of relapse rate and probably may decrease the risk of disability progression.52,53 Natalizumab has been also used in adolescents with MS.54–58 The largest series published so far included 55 pediatric MS patients, of whom only 3 patients experienced a relapse during the treatment period.57 In another series, disease activity returned within 6 months following treatment cessation in six of eight patients.58 Neuropediatrics
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The use of natalizumab is limited by the risk of progressive multifocal leukoencephalopathy (PML) occurring in more than 2:1,000 patients.59 Assessment of the John Cunningham virusantibody status may help for risk stratification in patients treated with natalizumab.60–62 Children and adolescents have lower JC virus infection rates than adults,63 but data regarding the JC antibody status in children as determined by the currently used Stratify test (STRATIFY JCV, Biogen Idec, Weston, Massachusetts, United States) are limited.57 Fingolimod, the first approved oral agent for the treatment of MS, has shown to reduce relapse activity by 54% compared with placebo and has a profound effect on MR activity.64,65 It was approved in Europe in 2010 for adults with active RRMS. Fingolimod binds to the sphingosine-1-phosphate receptor on lymphocytes, preventing lymphocyte egress from lymph nodes. This results in a profound decrease in the number of peripherally circulating lymphocytes and therefore prevents autoaggressive lymphocytes from entering into the brain. Two patients developed severe varicella-zoster exacerbation, suggesting that fingolimod may have significant immunosuppressive effects.66 Furthermore, fingolimod induces a transient decrease of the heart rate after first dose administration. As in the postmarketing surveillance, two unexplained deaths during sleep occurred, in which a relation to fingolimod could not be ruled out, the Food and Drug Administration and European Medicines Agency announced new contraindication for its use in patients with certain cardiac conditions.67 Because of these safety concerns, the use of fingolimod should be undertaken after a serious riskbenefit evaluation.66 There is no information regarding safety, tolerability, and efficacy available in children yet. However, it is very likely that fingolimod will be of growing importance in the near future as seen in adult MS. Cyclophosphamide, although used for a long time is not approved for the treatment of MS. In a retrospective survey of 17 children, the relapse rate as well as disability as measured by the EDSS improved within the year following treatment initiation.68 However, patients under treatment with cyclophosphamide are exposed to an increased risk of infections, amenorrhea, bladder cancer, and secondary malignancies. Furthermore, immunosuppressive treatment may limit a subsequent use of natalizumab, since prior use of immunosuppression is a risk factor for the development of PML.60 Mitoxantrone, which is approved in adults with highly active MS69 has been applied in four pediatric MS patients so far.70 However, its use is not recommended in children because of its cardiotoxicity and the risk of secondary leukaemia.15
Emerging Therapies Several new oral agents as well as monoclonal antibodies have been developed and for some of them, approval is awaited shortly. However, none of these agents is currently being tested in pediatric MS. Dimethyl fumarate, the active compound of BG-12, which may enhance the cellular response against oxidative stress, demonstrated a 50% reduction of relapse rates compared with placebo paralleled by a reduction of new lesion formation on
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MRI.71,72 Flushing and gastrointestinal symptoms such as nausea, abdominal pain, and diarrhea were the most common reported side effects during the first months of treatment.71,72 Two cases of PML occurring during fumaric acid ester treatment in patients with psoriasis were recently described.73,74 However, there have been no cases of PML reported in the context of RRMS treated with dimethyl fumarate. Teriflunomide, which reduces the activity of proliferating T and B lymphocytes, therefore, diminishing the inflammatory response to autoantigens, decreased the annualized relapse rate for 31% compared with placebo.75,76 It has been well tolerated in adults, although elevation of transaminases and alopecia occurred. However, risk of teratogenicity may caution its use in women of childbearing age.66 Laquinimod, which may exhibit both immunomodulatory and neuroprotective properties, has a moderate efficacy in reducing relapse rate, but it may have a more pronounced effect in reducing sustained disability progression and brain atrophy.77,78 Rituximab has shown efficacy in phase II trials in adults79; however, more than 50 cases of PML have been reported.80 Reduction in relapse rate has been also reported in a pediatric MS patient.81 Alemtuzumab, a humanized monoclonal antibody targeting CD52, has demonstrated a clear superiority against subcutaneous interferon β-1a in term of relapse and MR activity.82,83 However, infusion-related reactions, secondary autoimmunity, and infection require enhanced-treatment monitoring. Daclizumab, a humanized monoclonal antibody specific for the interleukin 2-receptor α chain, has been tested in phase II trials in adult MS,84,85 whereas the results of the phase III trial are awaited. It has been shown to be only partially effective in seven pediatric MS patients with breakthrough disease.86
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Management of Pediatric MS Patients 16
Limited efficacy, side effects, intramuscular, or subcutaneous application, as well as the need of treatment continuation even in periods of stable disease may influence treatment adherence. Adherence to injectable therapies in adult MS has been shown to range between 60 and 80%.87 A recent survey on 258 pediatric patients found that 16% of the patients discontinued therapy because of side effects or reduced compliance after a mean treatment period of 1.1 years.51 The high frequency of change of therapy because of breakthrough disease, nontolerance or poor compliance, as well as missing long-term safety data of first-line and second-line agents underline the need for controlled trials in pediatric patients with MS.
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