Disease modifying therapies in multiple sclerosis: Report of the therapeutics and technology assessment subcommittee of the American academy of neurology and the MS council for clinical practice guidelines

D. S. Goodin, Elliot Frohman, G. P. Garmany, J. Halper, W. H. Likosky, F. D. Lublin, D. H. Silberberg, W. H. Stuart, S. Van Den Noort

Research output: Contribution to journalArticle

709 Citations (Scopus)

Abstract

Glucocorticoids: 1. On the basis of several and generally consistent Class I and Class II studies, glucocorticoid treatment has been demonstrated to have a short-term benefit on the speed of functional recovery in patients with acute attacks of MS. It is appropriate, therefore, to consider for treatment with glucocorticoids any patient with an acute attack of MS (Type A recommendation). 2. There does not appear, however, to be any long-term functional benefit after the brief use of glucocorticoids in this clinical setting (Type B recommendation). 3. Currently, there is not compelling evidence to indicate that these clinical benefits are influenced by the route of glucocorticoid administration, the particular glucocorticoid prescribed, or the dosage of glucocorticoid, at least at the doses that have been studied to date (Type C recommendation). 4. On the basis of a single Class II study, it is considered possible that regular pulse glucocorticoids may be useful in the long-term management of patients with RRMS (Type C recommendation). Interferon beta: 1. On the basis of several consistent Class I studies, IFNβ has been demonstrated to reduce the attack rate (whether measured clinically or by MRI) in patients with MS or with clinically isolated syndromes who are at high risk for developing MS (Type A recommendation). Treatment of MS with IFNβ produces a beneficial effect on MRI measures of disease severity such as T2 disease burden and probably also slows sustained disability progression (Type B recommendation). 2. As a result, it is appropriate to consider IFNβ for treatment in any patient who is at high risk for developing CDMS, or who already has either RRMS or SPMS and is still experiencing relapses (Type A recommendation). The effectiveness of IFNβ in patients with SPMS but without relapses is uncertain (Type U recommendation). 3. It is possible that certain populations of MS patients (e.g., those with more attacks or at earlier disease stages) may be better candidates for therapy than others, although, at the moment, there is insufficient evidence regarding these issues (Type U Recommendation). 4. On the basis of Class I and II studies and several pieces of consistent Class III evidence, it is considered probable that there is a dose-response curve associated with the use of IFNβ for the treatment of MS (Type B recommendation). It is possible, however, that a portion of this apparent dose-effect instead may be due to differences in the frequency of IFNβ administration (rather than dose) between studies. 5. On the basis of several Class II studies, the route of administration of IFNβ is probably not of clinical importance, at least with regard to efficacy (Type B recommendation). The side-effect profile, however, does differ between routes of administration. There is no known clinical difference between the different types of IFNβ, although this has not been thoroughly studied (Type U recommendation). 6. On the basis of several Class I studies, treatment of patients with MS with IFNβ is associated with the production of NAb (Type A recommendation). The rate of NAb production, however, is probably less with IFNβ-1a treatment than with IFNβ-1b treatment (Type B recommendation). The biologic effect of NAb is uncertain, although their presence may be associated with a reduction in clinical effectiveness of IFNβ treatment (Type C recommendation). Whether there is a difference in immunogenicity between subcutaneous and intramuscular routes of administration is unknown (Type U recommendation). The clinical utility of measuring NAb in an individual on IFNβ therapy is uncertain (Type U recommendation). Glatiramer acetate: 1. On the basis of Class I evidence, glatiramer acetate has been demonstrated to reduce the attack rate (whether measured clinically or by MRI) in patients with RRMS (Type A recommendation). Treatment with glatiramer acetate produces a beneficial effect on MRI measures of disease severity, such as T2 disease burden, and possibly also slows sustained disability progression in patients with RRMS (Type C recommendation). 2. As a result, it is appropriate to consider glatiramer acetate for treatment in any patient who has RRMS (Type A recommendation). Although it may be that glatiramer acetate also is helpful in patients with progressive disease, there is no convincing evidence to support this hypothesis (Type U Recommendation). Cyclophosphamide: 1. Based on consistent Class I evidence, pulse cyclophosphamide treatment does not seem to alter the course of progressive MS (Type B recommendation). 2. Based on a single Class III study, it is possible that younger patients with progressive MS might derive some benefit from pulse plus booster cyclophosphamide treatment (Type U recommendation). Methotrexate: 1. Based on limited and somewhat ambiguous Class I evidence from a single trial, it is considered possible that methotrexate favorably alters the disease course in patients with progressive MS (Type C recommendation). Azathioprine: 1. On the basis of several, but somewhat conflicting, Class I and II studies, it is considered possible that azathioprine reduces the relapse rate in patients with MS (Type C recommendation). 2. Its effect on disability progression has not been demonstrated (Type U recommendation). Cladribine: 1. On the basis of consistent Class I evidence, it is concluded that cladribine reduces Gd enhancement in patients with both relapsing and progressive forms of MS (Type A recommendation). 2. Cladribine treatment does not, however, appear to alter favorably the course of the disease, either in terms of attack rate or disease progression (Type C recommendation). Cyclosporine: 1. Based on this Class I study, it is considered possible that cyclosporine provides some therapeutic benefit in progressive MS (Type C recommendation). 2. However, the frequent occurrence of adverse reactions to treatment, especially nephrotoxicity, together with the small magnitude of the potential benefit, makes the risk/benefit of this therapeutic approach unacceptable (Type B recommendation). Mitoxantrone: 1. On the basis of generally consistent Class II and III studies, it is concluded that mitoxantrone probably reduces the attack rate in patients with relapsing forms of MS (Type B recommendation). The potential toxicity of mitoxantrone, however, may outweigh the clinical benefits early in the course of disease. 2. On the basis of several Class II and III observations, it is considered possible that mitoxantrone has a beneficial effect on disease progression in MS, although, at the moment, this clinical benefit has not been established (Type C recommendation). Intravenous immunoglobulin: 1. The studies of intravenous immunoglobulin (IVIg), to date, have generally involved small numbers of patients, have lacked complete data on clinical and MRI outcomes, or have used methods that have been questioned. It is, therefore, only possible that IVIg reduces the attack rate in RRMS (Type C recommendation). 2. The current evidence suggests that IVIg is of little benefit with regard to slowing disease progression (Type C recommendation). Plasma exchange: 1. On the basis of consistent Class I, II, and III studies, plasma exchange is of little or no value in the treatment of progressive MS (Type A recommendation). 2. On the basis of a single small Class I study, it is considered possible that plasma exchange may be helpful in the treatment of severe acute episodes of demyelination in previously nondisabled individuals (Type C recommendation). Sulfasalazine: 1. Based on a single Class I study, it is concluded that treatment of MS with sulfasalazine provides no therapeutic benefit in MS (Type B recommendation).

Original languageEnglish (US)
Pages (from-to)169-178
Number of pages10
JournalNeurology
Volume58
Issue number2
StatePublished - Jan 22 2002

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Biomedical Technology Assessment
Neurology
Practice Guidelines
Multiple Sclerosis
Glucocorticoids
Therapeutics
Mitoxantrone
Intravenous Immunoglobulins
Cladribine
Plasma Exchange
Cyclophosphamide
Disease Progression
Sulfasalazine
Azathioprine
Methotrexate
Recurrence
Cyclosporine

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Disease modifying therapies in multiple sclerosis : Report of the therapeutics and technology assessment subcommittee of the American academy of neurology and the MS council for clinical practice guidelines. / Goodin, D. S.; Frohman, Elliot; Garmany, G. P.; Halper, J.; Likosky, W. H.; Lublin, F. D.; Silberberg, D. H.; Stuart, W. H.; Van Den Noort, S.

In: Neurology, Vol. 58, No. 2, 22.01.2002, p. 169-178.

Research output: Contribution to journalArticle

Goodin, D. S. ; Frohman, Elliot ; Garmany, G. P. ; Halper, J. ; Likosky, W. H. ; Lublin, F. D. ; Silberberg, D. H. ; Stuart, W. H. ; Van Den Noort, S. / Disease modifying therapies in multiple sclerosis : Report of the therapeutics and technology assessment subcommittee of the American academy of neurology and the MS council for clinical practice guidelines. In: Neurology. 2002 ; Vol. 58, No. 2. pp. 169-178.
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abstract = "Glucocorticoids: 1. On the basis of several and generally consistent Class I and Class II studies, glucocorticoid treatment has been demonstrated to have a short-term benefit on the speed of functional recovery in patients with acute attacks of MS. It is appropriate, therefore, to consider for treatment with glucocorticoids any patient with an acute attack of MS (Type A recommendation). 2. There does not appear, however, to be any long-term functional benefit after the brief use of glucocorticoids in this clinical setting (Type B recommendation). 3. Currently, there is not compelling evidence to indicate that these clinical benefits are influenced by the route of glucocorticoid administration, the particular glucocorticoid prescribed, or the dosage of glucocorticoid, at least at the doses that have been studied to date (Type C recommendation). 4. On the basis of a single Class II study, it is considered possible that regular pulse glucocorticoids may be useful in the long-term management of patients with RRMS (Type C recommendation). Interferon beta: 1. On the basis of several consistent Class I studies, IFNβ has been demonstrated to reduce the attack rate (whether measured clinically or by MRI) in patients with MS or with clinically isolated syndromes who are at high risk for developing MS (Type A recommendation). Treatment of MS with IFNβ produces a beneficial effect on MRI measures of disease severity such as T2 disease burden and probably also slows sustained disability progression (Type B recommendation). 2. As a result, it is appropriate to consider IFNβ for treatment in any patient who is at high risk for developing CDMS, or who already has either RRMS or SPMS and is still experiencing relapses (Type A recommendation). The effectiveness of IFNβ in patients with SPMS but without relapses is uncertain (Type U recommendation). 3. It is possible that certain populations of MS patients (e.g., those with more attacks or at earlier disease stages) may be better candidates for therapy than others, although, at the moment, there is insufficient evidence regarding these issues (Type U Recommendation). 4. On the basis of Class I and II studies and several pieces of consistent Class III evidence, it is considered probable that there is a dose-response curve associated with the use of IFNβ for the treatment of MS (Type B recommendation). It is possible, however, that a portion of this apparent dose-effect instead may be due to differences in the frequency of IFNβ administration (rather than dose) between studies. 5. On the basis of several Class II studies, the route of administration of IFNβ is probably not of clinical importance, at least with regard to efficacy (Type B recommendation). The side-effect profile, however, does differ between routes of administration. There is no known clinical difference between the different types of IFNβ, although this has not been thoroughly studied (Type U recommendation). 6. On the basis of several Class I studies, treatment of patients with MS with IFNβ is associated with the production of NAb (Type A recommendation). The rate of NAb production, however, is probably less with IFNβ-1a treatment than with IFNβ-1b treatment (Type B recommendation). The biologic effect of NAb is uncertain, although their presence may be associated with a reduction in clinical effectiveness of IFNβ treatment (Type C recommendation). Whether there is a difference in immunogenicity between subcutaneous and intramuscular routes of administration is unknown (Type U recommendation). The clinical utility of measuring NAb in an individual on IFNβ therapy is uncertain (Type U recommendation). Glatiramer acetate: 1. On the basis of Class I evidence, glatiramer acetate has been demonstrated to reduce the attack rate (whether measured clinically or by MRI) in patients with RRMS (Type A recommendation). Treatment with glatiramer acetate produces a beneficial effect on MRI measures of disease severity, such as T2 disease burden, and possibly also slows sustained disability progression in patients with RRMS (Type C recommendation). 2. As a result, it is appropriate to consider glatiramer acetate for treatment in any patient who has RRMS (Type A recommendation). Although it may be that glatiramer acetate also is helpful in patients with progressive disease, there is no convincing evidence to support this hypothesis (Type U Recommendation). Cyclophosphamide: 1. Based on consistent Class I evidence, pulse cyclophosphamide treatment does not seem to alter the course of progressive MS (Type B recommendation). 2. Based on a single Class III study, it is possible that younger patients with progressive MS might derive some benefit from pulse plus booster cyclophosphamide treatment (Type U recommendation). Methotrexate: 1. Based on limited and somewhat ambiguous Class I evidence from a single trial, it is considered possible that methotrexate favorably alters the disease course in patients with progressive MS (Type C recommendation). Azathioprine: 1. On the basis of several, but somewhat conflicting, Class I and II studies, it is considered possible that azathioprine reduces the relapse rate in patients with MS (Type C recommendation). 2. Its effect on disability progression has not been demonstrated (Type U recommendation). Cladribine: 1. On the basis of consistent Class I evidence, it is concluded that cladribine reduces Gd enhancement in patients with both relapsing and progressive forms of MS (Type A recommendation). 2. Cladribine treatment does not, however, appear to alter favorably the course of the disease, either in terms of attack rate or disease progression (Type C recommendation). Cyclosporine: 1. Based on this Class I study, it is considered possible that cyclosporine provides some therapeutic benefit in progressive MS (Type C recommendation). 2. However, the frequent occurrence of adverse reactions to treatment, especially nephrotoxicity, together with the small magnitude of the potential benefit, makes the risk/benefit of this therapeutic approach unacceptable (Type B recommendation). Mitoxantrone: 1. On the basis of generally consistent Class II and III studies, it is concluded that mitoxantrone probably reduces the attack rate in patients with relapsing forms of MS (Type B recommendation). The potential toxicity of mitoxantrone, however, may outweigh the clinical benefits early in the course of disease. 2. On the basis of several Class II and III observations, it is considered possible that mitoxantrone has a beneficial effect on disease progression in MS, although, at the moment, this clinical benefit has not been established (Type C recommendation). Intravenous immunoglobulin: 1. The studies of intravenous immunoglobulin (IVIg), to date, have generally involved small numbers of patients, have lacked complete data on clinical and MRI outcomes, or have used methods that have been questioned. It is, therefore, only possible that IVIg reduces the attack rate in RRMS (Type C recommendation). 2. The current evidence suggests that IVIg is of little benefit with regard to slowing disease progression (Type C recommendation). Plasma exchange: 1. On the basis of consistent Class I, II, and III studies, plasma exchange is of little or no value in the treatment of progressive MS (Type A recommendation). 2. On the basis of a single small Class I study, it is considered possible that plasma exchange may be helpful in the treatment of severe acute episodes of demyelination in previously nondisabled individuals (Type C recommendation). Sulfasalazine: 1. Based on a single Class I study, it is concluded that treatment of MS with sulfasalazine provides no therapeutic benefit in MS (Type B recommendation).",
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T1 - Disease modifying therapies in multiple sclerosis

T2 - Report of the therapeutics and technology assessment subcommittee of the American academy of neurology and the MS council for clinical practice guidelines

AU - Goodin, D. S.

AU - Frohman, Elliot

AU - Garmany, G. P.

AU - Halper, J.

AU - Likosky, W. H.

AU - Lublin, F. D.

AU - Silberberg, D. H.

AU - Stuart, W. H.

AU - Van Den Noort, S.

PY - 2002/1/22

Y1 - 2002/1/22

N2 - Glucocorticoids: 1. On the basis of several and generally consistent Class I and Class II studies, glucocorticoid treatment has been demonstrated to have a short-term benefit on the speed of functional recovery in patients with acute attacks of MS. It is appropriate, therefore, to consider for treatment with glucocorticoids any patient with an acute attack of MS (Type A recommendation). 2. There does not appear, however, to be any long-term functional benefit after the brief use of glucocorticoids in this clinical setting (Type B recommendation). 3. Currently, there is not compelling evidence to indicate that these clinical benefits are influenced by the route of glucocorticoid administration, the particular glucocorticoid prescribed, or the dosage of glucocorticoid, at least at the doses that have been studied to date (Type C recommendation). 4. On the basis of a single Class II study, it is considered possible that regular pulse glucocorticoids may be useful in the long-term management of patients with RRMS (Type C recommendation). Interferon beta: 1. On the basis of several consistent Class I studies, IFNβ has been demonstrated to reduce the attack rate (whether measured clinically or by MRI) in patients with MS or with clinically isolated syndromes who are at high risk for developing MS (Type A recommendation). Treatment of MS with IFNβ produces a beneficial effect on MRI measures of disease severity such as T2 disease burden and probably also slows sustained disability progression (Type B recommendation). 2. As a result, it is appropriate to consider IFNβ for treatment in any patient who is at high risk for developing CDMS, or who already has either RRMS or SPMS and is still experiencing relapses (Type A recommendation). The effectiveness of IFNβ in patients with SPMS but without relapses is uncertain (Type U recommendation). 3. It is possible that certain populations of MS patients (e.g., those with more attacks or at earlier disease stages) may be better candidates for therapy than others, although, at the moment, there is insufficient evidence regarding these issues (Type U Recommendation). 4. On the basis of Class I and II studies and several pieces of consistent Class III evidence, it is considered probable that there is a dose-response curve associated with the use of IFNβ for the treatment of MS (Type B recommendation). It is possible, however, that a portion of this apparent dose-effect instead may be due to differences in the frequency of IFNβ administration (rather than dose) between studies. 5. On the basis of several Class II studies, the route of administration of IFNβ is probably not of clinical importance, at least with regard to efficacy (Type B recommendation). The side-effect profile, however, does differ between routes of administration. There is no known clinical difference between the different types of IFNβ, although this has not been thoroughly studied (Type U recommendation). 6. On the basis of several Class I studies, treatment of patients with MS with IFNβ is associated with the production of NAb (Type A recommendation). The rate of NAb production, however, is probably less with IFNβ-1a treatment than with IFNβ-1b treatment (Type B recommendation). The biologic effect of NAb is uncertain, although their presence may be associated with a reduction in clinical effectiveness of IFNβ treatment (Type C recommendation). Whether there is a difference in immunogenicity between subcutaneous and intramuscular routes of administration is unknown (Type U recommendation). The clinical utility of measuring NAb in an individual on IFNβ therapy is uncertain (Type U recommendation). Glatiramer acetate: 1. On the basis of Class I evidence, glatiramer acetate has been demonstrated to reduce the attack rate (whether measured clinically or by MRI) in patients with RRMS (Type A recommendation). Treatment with glatiramer acetate produces a beneficial effect on MRI measures of disease severity, such as T2 disease burden, and possibly also slows sustained disability progression in patients with RRMS (Type C recommendation). 2. As a result, it is appropriate to consider glatiramer acetate for treatment in any patient who has RRMS (Type A recommendation). Although it may be that glatiramer acetate also is helpful in patients with progressive disease, there is no convincing evidence to support this hypothesis (Type U Recommendation). Cyclophosphamide: 1. Based on consistent Class I evidence, pulse cyclophosphamide treatment does not seem to alter the course of progressive MS (Type B recommendation). 2. Based on a single Class III study, it is possible that younger patients with progressive MS might derive some benefit from pulse plus booster cyclophosphamide treatment (Type U recommendation). Methotrexate: 1. Based on limited and somewhat ambiguous Class I evidence from a single trial, it is considered possible that methotrexate favorably alters the disease course in patients with progressive MS (Type C recommendation). Azathioprine: 1. On the basis of several, but somewhat conflicting, Class I and II studies, it is considered possible that azathioprine reduces the relapse rate in patients with MS (Type C recommendation). 2. Its effect on disability progression has not been demonstrated (Type U recommendation). Cladribine: 1. On the basis of consistent Class I evidence, it is concluded that cladribine reduces Gd enhancement in patients with both relapsing and progressive forms of MS (Type A recommendation). 2. Cladribine treatment does not, however, appear to alter favorably the course of the disease, either in terms of attack rate or disease progression (Type C recommendation). Cyclosporine: 1. Based on this Class I study, it is considered possible that cyclosporine provides some therapeutic benefit in progressive MS (Type C recommendation). 2. However, the frequent occurrence of adverse reactions to treatment, especially nephrotoxicity, together with the small magnitude of the potential benefit, makes the risk/benefit of this therapeutic approach unacceptable (Type B recommendation). Mitoxantrone: 1. On the basis of generally consistent Class II and III studies, it is concluded that mitoxantrone probably reduces the attack rate in patients with relapsing forms of MS (Type B recommendation). The potential toxicity of mitoxantrone, however, may outweigh the clinical benefits early in the course of disease. 2. On the basis of several Class II and III observations, it is considered possible that mitoxantrone has a beneficial effect on disease progression in MS, although, at the moment, this clinical benefit has not been established (Type C recommendation). Intravenous immunoglobulin: 1. The studies of intravenous immunoglobulin (IVIg), to date, have generally involved small numbers of patients, have lacked complete data on clinical and MRI outcomes, or have used methods that have been questioned. It is, therefore, only possible that IVIg reduces the attack rate in RRMS (Type C recommendation). 2. The current evidence suggests that IVIg is of little benefit with regard to slowing disease progression (Type C recommendation). Plasma exchange: 1. On the basis of consistent Class I, II, and III studies, plasma exchange is of little or no value in the treatment of progressive MS (Type A recommendation). 2. On the basis of a single small Class I study, it is considered possible that plasma exchange may be helpful in the treatment of severe acute episodes of demyelination in previously nondisabled individuals (Type C recommendation). Sulfasalazine: 1. Based on a single Class I study, it is concluded that treatment of MS with sulfasalazine provides no therapeutic benefit in MS (Type B recommendation).

AB - Glucocorticoids: 1. On the basis of several and generally consistent Class I and Class II studies, glucocorticoid treatment has been demonstrated to have a short-term benefit on the speed of functional recovery in patients with acute attacks of MS. It is appropriate, therefore, to consider for treatment with glucocorticoids any patient with an acute attack of MS (Type A recommendation). 2. There does not appear, however, to be any long-term functional benefit after the brief use of glucocorticoids in this clinical setting (Type B recommendation). 3. Currently, there is not compelling evidence to indicate that these clinical benefits are influenced by the route of glucocorticoid administration, the particular glucocorticoid prescribed, or the dosage of glucocorticoid, at least at the doses that have been studied to date (Type C recommendation). 4. On the basis of a single Class II study, it is considered possible that regular pulse glucocorticoids may be useful in the long-term management of patients with RRMS (Type C recommendation). Interferon beta: 1. On the basis of several consistent Class I studies, IFNβ has been demonstrated to reduce the attack rate (whether measured clinically or by MRI) in patients with MS or with clinically isolated syndromes who are at high risk for developing MS (Type A recommendation). Treatment of MS with IFNβ produces a beneficial effect on MRI measures of disease severity such as T2 disease burden and probably also slows sustained disability progression (Type B recommendation). 2. As a result, it is appropriate to consider IFNβ for treatment in any patient who is at high risk for developing CDMS, or who already has either RRMS or SPMS and is still experiencing relapses (Type A recommendation). The effectiveness of IFNβ in patients with SPMS but without relapses is uncertain (Type U recommendation). 3. It is possible that certain populations of MS patients (e.g., those with more attacks or at earlier disease stages) may be better candidates for therapy than others, although, at the moment, there is insufficient evidence regarding these issues (Type U Recommendation). 4. On the basis of Class I and II studies and several pieces of consistent Class III evidence, it is considered probable that there is a dose-response curve associated with the use of IFNβ for the treatment of MS (Type B recommendation). It is possible, however, that a portion of this apparent dose-effect instead may be due to differences in the frequency of IFNβ administration (rather than dose) between studies. 5. On the basis of several Class II studies, the route of administration of IFNβ is probably not of clinical importance, at least with regard to efficacy (Type B recommendation). The side-effect profile, however, does differ between routes of administration. There is no known clinical difference between the different types of IFNβ, although this has not been thoroughly studied (Type U recommendation). 6. On the basis of several Class I studies, treatment of patients with MS with IFNβ is associated with the production of NAb (Type A recommendation). The rate of NAb production, however, is probably less with IFNβ-1a treatment than with IFNβ-1b treatment (Type B recommendation). The biologic effect of NAb is uncertain, although their presence may be associated with a reduction in clinical effectiveness of IFNβ treatment (Type C recommendation). Whether there is a difference in immunogenicity between subcutaneous and intramuscular routes of administration is unknown (Type U recommendation). The clinical utility of measuring NAb in an individual on IFNβ therapy is uncertain (Type U recommendation). Glatiramer acetate: 1. On the basis of Class I evidence, glatiramer acetate has been demonstrated to reduce the attack rate (whether measured clinically or by MRI) in patients with RRMS (Type A recommendation). Treatment with glatiramer acetate produces a beneficial effect on MRI measures of disease severity, such as T2 disease burden, and possibly also slows sustained disability progression in patients with RRMS (Type C recommendation). 2. As a result, it is appropriate to consider glatiramer acetate for treatment in any patient who has RRMS (Type A recommendation). Although it may be that glatiramer acetate also is helpful in patients with progressive disease, there is no convincing evidence to support this hypothesis (Type U Recommendation). Cyclophosphamide: 1. Based on consistent Class I evidence, pulse cyclophosphamide treatment does not seem to alter the course of progressive MS (Type B recommendation). 2. Based on a single Class III study, it is possible that younger patients with progressive MS might derive some benefit from pulse plus booster cyclophosphamide treatment (Type U recommendation). Methotrexate: 1. Based on limited and somewhat ambiguous Class I evidence from a single trial, it is considered possible that methotrexate favorably alters the disease course in patients with progressive MS (Type C recommendation). Azathioprine: 1. On the basis of several, but somewhat conflicting, Class I and II studies, it is considered possible that azathioprine reduces the relapse rate in patients with MS (Type C recommendation). 2. Its effect on disability progression has not been demonstrated (Type U recommendation). Cladribine: 1. On the basis of consistent Class I evidence, it is concluded that cladribine reduces Gd enhancement in patients with both relapsing and progressive forms of MS (Type A recommendation). 2. Cladribine treatment does not, however, appear to alter favorably the course of the disease, either in terms of attack rate or disease progression (Type C recommendation). Cyclosporine: 1. Based on this Class I study, it is considered possible that cyclosporine provides some therapeutic benefit in progressive MS (Type C recommendation). 2. However, the frequent occurrence of adverse reactions to treatment, especially nephrotoxicity, together with the small magnitude of the potential benefit, makes the risk/benefit of this therapeutic approach unacceptable (Type B recommendation). Mitoxantrone: 1. On the basis of generally consistent Class II and III studies, it is concluded that mitoxantrone probably reduces the attack rate in patients with relapsing forms of MS (Type B recommendation). The potential toxicity of mitoxantrone, however, may outweigh the clinical benefits early in the course of disease. 2. On the basis of several Class II and III observations, it is considered possible that mitoxantrone has a beneficial effect on disease progression in MS, although, at the moment, this clinical benefit has not been established (Type C recommendation). Intravenous immunoglobulin: 1. The studies of intravenous immunoglobulin (IVIg), to date, have generally involved small numbers of patients, have lacked complete data on clinical and MRI outcomes, or have used methods that have been questioned. It is, therefore, only possible that IVIg reduces the attack rate in RRMS (Type C recommendation). 2. The current evidence suggests that IVIg is of little benefit with regard to slowing disease progression (Type C recommendation). Plasma exchange: 1. On the basis of consistent Class I, II, and III studies, plasma exchange is of little or no value in the treatment of progressive MS (Type A recommendation). 2. On the basis of a single small Class I study, it is considered possible that plasma exchange may be helpful in the treatment of severe acute episodes of demyelination in previously nondisabled individuals (Type C recommendation). Sulfasalazine: 1. Based on a single Class I study, it is concluded that treatment of MS with sulfasalazine provides no therapeutic benefit in MS (Type B recommendation).

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