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Interferon β therapy for multiple sclerosis
COMMENTARY
COMMENTARY
Interferon therapy for multiple sclerosis See pages 1491, 1498 Multiple sclerosis affects 300 000 people in the USA and 1·1 million worldwide. The clinical patterns of this illness1 are illustrated in the figure. About 85% of patients initially experience a relapsing-remitting clinical course (A, B). This phase begins with one or more exacerbations followed by complete or partial recovery and, during this phase, patients are clinically stable between relapses. Within 10 years, 50% of relapsing-remitting patients experience gradual progression of disability with or without superimposed relapses (D, C). These patterns are called secondary-progressive. The remaining 15% of patients experience a clinical course that is progressive from onset, with or without relapses—patterns known as primary-progressive (E, F) and progressive-relapsing (G), respectively. Disease-modifying treatments are now available for patients with multiple sclerosis. Interferon -1a 6·0106 IU intramuscularly each week, interferon -1b 8·0106 IU subcutaneously every other day, or glatiramer acetate 20 mg subcutaneously every day significantly reduces the frequency of exacerbations in patients with relapsing-remitting disease.2–4 Interferon -1a also significantly delays time to onset of sustained progression of disability in such patients.2 These disease-modifying treatment options are also prescribed for patients with secondary progressive multiple sclerosis who experience superimposed relapses during the preceding 1 or 2 years (pattern D). There is a notion that early treatment is desirable because interferons -1a and -1b greatly reduce the number of new focal lesions on magnetic resonance imaging (MRI),5,6 which reflect varying amounts of reversible oedema and inflammation and irreversible demyelination and axonal transection within plaques.5–7 The cumulative effects of irreversible histopathological changes in plaques are thought to be at
Patterns of multiple sclerosis
Pattern of disability
A
Relapsing-remitting
B Secondary-progressive
C D
Primary-progressive
E
Progressive-relapsing
F G Time
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least partly responsible for gradual progression of disability. The results of two phase III trials of interferon -1a and interferon -1b for multiple sclerosis are reported in this issue of The Lancet. The PRISMS trial confirms earlier reports that interferon -1a reduces clinical relapse rate, delays time to onset of sustained progression of disability, and reduces the number of new MRI lesions in patients with relapsing-remitting multiple sclerosis. This study also suggests that some treatment benefits may be dose related, a consideration that merits careful scrutiny. The European multicentre trial of interferon -1b in secondary-progressive disease (European SP trial) indicates that treatment significantly delays time to onset of sustained progression of disease and significantly reduces relapse rate, number of new MRI lesions, and progression of total T2-weighted lesion load. These results justify expanding the indications for interferon -1b to patients with secondary-progressive multiple sclerosis even if they have not experienced superimposed relapses (pattern C). Not everyone reading the PRISMS study will conclude that there is a clinically relevant dose-related effect favouring the high-dose regimen. High-dose patients do not respond better than low-dose recipients when the measures of efficacy are reduction in mean number of relapses, severity of relapses, odds ratio for likelihood of hospital admission, change in expanded disability status scale (EDSS), first quartile time to onset of sustained progression of disability, and median change in total T2-weighted MRI lesion burden, but they have fewer active T2 MRI lesions. And, when compared with low-dose recipients with EDSS scores greater than 3·5, high-dose recipients experience a longer time to onset of sustained progression of disability. How shall we reconcile these apparent inconsistencies? The reader may conclude that the apparent dose-related effect measured by MRI is difficult to interpret because details of MRI measures of interest at baseline and subsequent scanning sessions are not provided. Further, the dose-related clinical benefit is confined to a subgroup of less than 16% of patients who start therapy and are at risk of sustained progression of disability. The confirmation by PRISMS of the efficacy of interferon -1a in patients with relapsingremitting multiple sclerosis is reassuring, but the evidence for a clinically relevant dose-related treatment effect is not convincing. The European SP trial sends a cogent message. Patients with secondary-progressive multiple sclerosis benefit from interferon -1b whether or not they experience superimposed relapses for 2 years preceding therapy (patterns D and C). Thus, interferon -1b should immediately be made available for patients with THE LANCET • Vol 352 • November 7, 1998
COMMENTARY
secondary-progressive disease, including those who have not experienced superimposed relapses. We now need to find out whether the response to therapy is dose related. This question may be answered by comparing time to onset of sustained progression of disability in the highdose and low-dose groups in the current North American phase III trial of interferon -1b in secondary-progressive multiple sclerosis (North American SP trial). The opportunity to find out the most effective dose of interferon -1b is sufficient reason to continue the active treatment arms of this North American trial in compliance with the study protocol. How should we treat patients with relapsing-remitting or secondary-progressive multiple sclerosis who continue to experience gradual progression of disability despite treatment with interferon -1a or -1b? This is not a trivial question because about 20% of patients with relapsing disease and 40% of those with secondaryprogressive multiple sclerosis will experience sustained progression of disability within 2 years of the start of treatment (reference 2 and the European SP trial). Glatiramer acetate is not an appealing treatment option for such patients because there is no convincing evidence of delay of time to onset of sustained progression of disability.4 Therefore, future clinical trials in relapsingremitting and secondary-progressive disease should be designed to assess relative efficacies of higher doses of interferon or to compare the efficacy of interferon with that of interferon plus other promising therapies. The PRISMS and European SP trials resurrect questions about the clinical significance of neutralising antibodies to interferon -1a and -1b. Why should there be a relation between antibody titre and dose for interferon -1a but not interferon -1b?3,8 Why is there no relation between titre of neutralising antibodies to interferon -1a and efficacy measured by change in relapse rate, when there is a significant relation for interferon -1b? Details of annual relapse rates and MRI activity in patients with and without neutralising antibodies must be provided before these questions can be answered.
Donald E Goodkin MS Center, Department of Neurology, University of California San Francisco, San Francisco, CA 94115, USA 1 2
3
4
5
6
7
8
Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology 1996; 46: 907–11. Jacobs LD, Cookfair DL, Rudick RA, et al, and the Multiple Sclerosis Research Group (MSCRG). Intramuscular interferon beta-1a for disease progression in exacerbating-remitting multiple sclerosis. Ann Neurol 1996; 39: 285–294. The IFN Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis I: clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993; 43: 655–61. Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicentre, double-blind, placebo-controlled trial. Neurology 1995; 45: 1268–76. Stone LA, Frank JA, Albert PS, et al. Characterization of MRI response to treatment with interferon beta-1b: contrast enhancing MRI lesion frequency as a primary outcome. Neurology 1997; 49: 862–69. Pozzilli C, Bastianello S, Koudriavtseva T, et al. Magnetic resonance imaging changes with recombinant human interferon beta-1a: a short term study in relapsing remitting multiple sclerosis. J Neurol Neurosurg Psychiatry 1996; 61: 251–58. Trapp BD, Peterson J, Ransohoff RM, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998; 228: 278–85. Petkau J, White R. Neutralizing antibodies and the efficacy of interferon beta-1b in relapsing-remitting multiple sclerosis. Mult Scler 1997; 3: 402 (abstr).
THE LANCET • Vol 352 • November 7, 1998
Leukotrienes and the brain See page 1514 Leukotrienes are chemical mediators derived from arachidonic acid. Bronchoconstriction is their bestknown effect and several antileukotriene drugs have recently been developed for use in asthma. Leukotrienes have been found in the brain but their function there is poorly understood. In today’s Lancet, E Mayatepek and B Flock report evidence for a defect of leukotriene synthesis in an infant with microcephaly and severe psychomotor retardation. Do the findings mean that leukotrienes are essential for normal brain development? In leukotriene synthesis (figure), the first enzyme, 5lipoxygenase, is expressed primarily in myeloid cells and these are the main source of leukotrienes. Some tissues that lack 5-lipoxygenase can also form leukotriene (LT) B4 and LTC4 after transcellular delivery of LTA4. Leukotriene production in the brain is well documented. It is associated with expression of 5lipoxygenase in neurons from various parts of the brain, especially the hippocampus.1 LTC4 has been found in highest concentrations in the hypothalamus and median eminence, whereas LTB4 production was distributed more uniformly throughout the brain.2,3 To date, only the receptor for LTB4 has been cloned.4 The cysteinyl leukotrienes (LTC4, LTD4, and LTE4) have at least two receptors, which have been studied most extensively in lung. Cysteinyl leukotriene 1 (cysLT1) receptors are blocked by most known antagonists and are present on airway smooth muscle, whereas cysLT2 receptors are present on pulmonary blood vessels. The main function of leukotrienes seems to be the mediation of inflammation and host defence. Thus, the cysteinyl leukotrienes stimulate formation of eosinophils and promote inflammation by increasing vascular permeability. They also cause bronchoconstriction and mucus secretion (presumably evolved to remove pathogens from the lungs) and contraction of intestinal smooth muscle (to remove gastrointestinal parasites).5 LTB4 is both a chemotactic factor and an activator of leucocytes. In the brain, leukotrienes may have neuromodulatory and neuroendocrine functions. A neuroendocrine role was first suggested by the demonstration of LTC4 and gonadotropin-releasing hormone (GnRH) in the same neurons of the median eminence in rats.2 Subsequent studies showed that release of luteinising hormone from pituitary cells in response to GnRH was mediated partly by leukotrienes. Leukotrienes were synergistic with other second messengers such as protein kinase C, and leukotriene antagonists reduced but did not abolish release of luteinising hormone.6 Neuromodulatory effects of LTC4 include prolonged excitation of cerebellar Purkinje cells. LTC4 has also been shown to mediate an inhibitory effect of the neuropeptide somatostatin on pyramidal neurons in the hippocampus.1,7 Again, more than one second messenger seems to be involved: 5-lipoxygenase inhibitors did not completely abolish the effects of somatostatin.7 In defects of leukotriene synthesis, one might expect abnormalities related to the functions outlined above. 5-lipoxygenase “knockout” mice, however, have a relatively normal phenotype.8 Complete 5-lipoxygenase deficiency did not affect either the fetal or the postnatal development of these mice, which seemed healthy and
1487
COMMENTARY
Interferon therapy for multiple sclerosis See pages 1491, 1498 Multiple sclerosis affects 300 000 people in the USA and 1·1 million worldwide. The clinical patterns of this illness1 are illustrated in the figure. About 85% of patients initially experience a relapsing-remitting clinical course (A, B). This phase begins with one or more exacerbations followed by complete or partial recovery and, during this phase, patients are clinically stable between relapses. Within 10 years, 50% of relapsing-remitting patients experience gradual progression of disability with or without superimposed relapses (D, C). These patterns are called secondary-progressive. The remaining 15% of patients experience a clinical course that is progressive from onset, with or without relapses—patterns known as primary-progressive (E, F) and progressive-relapsing (G), respectively. Disease-modifying treatments are now available for patients with multiple sclerosis. Interferon -1a 6·0106 IU intramuscularly each week, interferon -1b 8·0106 IU subcutaneously every other day, or glatiramer acetate 20 mg subcutaneously every day significantly reduces the frequency of exacerbations in patients with relapsing-remitting disease.2–4 Interferon -1a also significantly delays time to onset of sustained progression of disability in such patients.2 These disease-modifying treatment options are also prescribed for patients with secondary progressive multiple sclerosis who experience superimposed relapses during the preceding 1 or 2 years (pattern D). There is a notion that early treatment is desirable because interferons -1a and -1b greatly reduce the number of new focal lesions on magnetic resonance imaging (MRI),5,6 which reflect varying amounts of reversible oedema and inflammation and irreversible demyelination and axonal transection within plaques.5–7 The cumulative effects of irreversible histopathological changes in plaques are thought to be at
Patterns of multiple sclerosis
Pattern of disability
A
Relapsing-remitting
B Secondary-progressive
C D
Primary-progressive
E
Progressive-relapsing
F G Time
1486
least partly responsible for gradual progression of disability. The results of two phase III trials of interferon -1a and interferon -1b for multiple sclerosis are reported in this issue of The Lancet. The PRISMS trial confirms earlier reports that interferon -1a reduces clinical relapse rate, delays time to onset of sustained progression of disability, and reduces the number of new MRI lesions in patients with relapsing-remitting multiple sclerosis. This study also suggests that some treatment benefits may be dose related, a consideration that merits careful scrutiny. The European multicentre trial of interferon -1b in secondary-progressive disease (European SP trial) indicates that treatment significantly delays time to onset of sustained progression of disease and significantly reduces relapse rate, number of new MRI lesions, and progression of total T2-weighted lesion load. These results justify expanding the indications for interferon -1b to patients with secondary-progressive multiple sclerosis even if they have not experienced superimposed relapses (pattern C). Not everyone reading the PRISMS study will conclude that there is a clinically relevant dose-related effect favouring the high-dose regimen. High-dose patients do not respond better than low-dose recipients when the measures of efficacy are reduction in mean number of relapses, severity of relapses, odds ratio for likelihood of hospital admission, change in expanded disability status scale (EDSS), first quartile time to onset of sustained progression of disability, and median change in total T2-weighted MRI lesion burden, but they have fewer active T2 MRI lesions. And, when compared with low-dose recipients with EDSS scores greater than 3·5, high-dose recipients experience a longer time to onset of sustained progression of disability. How shall we reconcile these apparent inconsistencies? The reader may conclude that the apparent dose-related effect measured by MRI is difficult to interpret because details of MRI measures of interest at baseline and subsequent scanning sessions are not provided. Further, the dose-related clinical benefit is confined to a subgroup of less than 16% of patients who start therapy and are at risk of sustained progression of disability. The confirmation by PRISMS of the efficacy of interferon -1a in patients with relapsingremitting multiple sclerosis is reassuring, but the evidence for a clinically relevant dose-related treatment effect is not convincing. The European SP trial sends a cogent message. Patients with secondary-progressive multiple sclerosis benefit from interferon -1b whether or not they experience superimposed relapses for 2 years preceding therapy (patterns D and C). Thus, interferon -1b should immediately be made available for patients with THE LANCET • Vol 352 • November 7, 1998
COMMENTARY
secondary-progressive disease, including those who have not experienced superimposed relapses. We now need to find out whether the response to therapy is dose related. This question may be answered by comparing time to onset of sustained progression of disability in the highdose and low-dose groups in the current North American phase III trial of interferon -1b in secondary-progressive multiple sclerosis (North American SP trial). The opportunity to find out the most effective dose of interferon -1b is sufficient reason to continue the active treatment arms of this North American trial in compliance with the study protocol. How should we treat patients with relapsing-remitting or secondary-progressive multiple sclerosis who continue to experience gradual progression of disability despite treatment with interferon -1a or -1b? This is not a trivial question because about 20% of patients with relapsing disease and 40% of those with secondaryprogressive multiple sclerosis will experience sustained progression of disability within 2 years of the start of treatment (reference 2 and the European SP trial). Glatiramer acetate is not an appealing treatment option for such patients because there is no convincing evidence of delay of time to onset of sustained progression of disability.4 Therefore, future clinical trials in relapsingremitting and secondary-progressive disease should be designed to assess relative efficacies of higher doses of interferon or to compare the efficacy of interferon with that of interferon plus other promising therapies. The PRISMS and European SP trials resurrect questions about the clinical significance of neutralising antibodies to interferon -1a and -1b. Why should there be a relation between antibody titre and dose for interferon -1a but not interferon -1b?3,8 Why is there no relation between titre of neutralising antibodies to interferon -1a and efficacy measured by change in relapse rate, when there is a significant relation for interferon -1b? Details of annual relapse rates and MRI activity in patients with and without neutralising antibodies must be provided before these questions can be answered.
Donald E Goodkin MS Center, Department of Neurology, University of California San Francisco, San Francisco, CA 94115, USA 1 2
3
4
5
6
7
8
Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology 1996; 46: 907–11. Jacobs LD, Cookfair DL, Rudick RA, et al, and the Multiple Sclerosis Research Group (MSCRG). Intramuscular interferon beta-1a for disease progression in exacerbating-remitting multiple sclerosis. Ann Neurol 1996; 39: 285–294. The IFN Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis I: clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993; 43: 655–61. Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicentre, double-blind, placebo-controlled trial. Neurology 1995; 45: 1268–76. Stone LA, Frank JA, Albert PS, et al. Characterization of MRI response to treatment with interferon beta-1b: contrast enhancing MRI lesion frequency as a primary outcome. Neurology 1997; 49: 862–69. Pozzilli C, Bastianello S, Koudriavtseva T, et al. Magnetic resonance imaging changes with recombinant human interferon beta-1a: a short term study in relapsing remitting multiple sclerosis. J Neurol Neurosurg Psychiatry 1996; 61: 251–58. Trapp BD, Peterson J, Ransohoff RM, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998; 228: 278–85. Petkau J, White R. Neutralizing antibodies and the efficacy of interferon beta-1b in relapsing-remitting multiple sclerosis. Mult Scler 1997; 3: 402 (abstr).
THE LANCET • Vol 352 • November 7, 1998
Leukotrienes and the brain See page 1514 Leukotrienes are chemical mediators derived from arachidonic acid. Bronchoconstriction is their bestknown effect and several antileukotriene drugs have recently been developed for use in asthma. Leukotrienes have been found in the brain but their function there is poorly understood. In today’s Lancet, E Mayatepek and B Flock report evidence for a defect of leukotriene synthesis in an infant with microcephaly and severe psychomotor retardation. Do the findings mean that leukotrienes are essential for normal brain development? In leukotriene synthesis (figure), the first enzyme, 5lipoxygenase, is expressed primarily in myeloid cells and these are the main source of leukotrienes. Some tissues that lack 5-lipoxygenase can also form leukotriene (LT) B4 and LTC4 after transcellular delivery of LTA4. Leukotriene production in the brain is well documented. It is associated with expression of 5lipoxygenase in neurons from various parts of the brain, especially the hippocampus.1 LTC4 has been found in highest concentrations in the hypothalamus and median eminence, whereas LTB4 production was distributed more uniformly throughout the brain.2,3 To date, only the receptor for LTB4 has been cloned.4 The cysteinyl leukotrienes (LTC4, LTD4, and LTE4) have at least two receptors, which have been studied most extensively in lung. Cysteinyl leukotriene 1 (cysLT1) receptors are blocked by most known antagonists and are present on airway smooth muscle, whereas cysLT2 receptors are present on pulmonary blood vessels. The main function of leukotrienes seems to be the mediation of inflammation and host defence. Thus, the cysteinyl leukotrienes stimulate formation of eosinophils and promote inflammation by increasing vascular permeability. They also cause bronchoconstriction and mucus secretion (presumably evolved to remove pathogens from the lungs) and contraction of intestinal smooth muscle (to remove gastrointestinal parasites).5 LTB4 is both a chemotactic factor and an activator of leucocytes. In the brain, leukotrienes may have neuromodulatory and neuroendocrine functions. A neuroendocrine role was first suggested by the demonstration of LTC4 and gonadotropin-releasing hormone (GnRH) in the same neurons of the median eminence in rats.2 Subsequent studies showed that release of luteinising hormone from pituitary cells in response to GnRH was mediated partly by leukotrienes. Leukotrienes were synergistic with other second messengers such as protein kinase C, and leukotriene antagonists reduced but did not abolish release of luteinising hormone.6 Neuromodulatory effects of LTC4 include prolonged excitation of cerebellar Purkinje cells. LTC4 has also been shown to mediate an inhibitory effect of the neuropeptide somatostatin on pyramidal neurons in the hippocampus.1,7 Again, more than one second messenger seems to be involved: 5-lipoxygenase inhibitors did not completely abolish the effects of somatostatin.7 In defects of leukotriene synthesis, one might expect abnormalities related to the functions outlined above. 5-lipoxygenase “knockout” mice, however, have a relatively normal phenotype.8 Complete 5-lipoxygenase deficiency did not affect either the fetal or the postnatal development of these mice, which seemed healthy and
1487