Selective Treatment of Multiple Sclerosis
http://www.100md.com
《新英格兰医药杂志》
Natalizumab, a recombinant monoclonal antibody against 4 integrins, is the first selective immunomodulating drug for the treatment of multiple sclerosis and, by several criteria, is an advance over current therapies. The antibody was developed to block the adhesion of activated T cells to endothelial cells and thereby reduce the inflammatory feature of the multiple sclerosis plaque. Parenthetically, this advance attests to the value of translational research in a disease for which there is only partial knowledge of the mechanism. Natalizumab has also evinced interest for the treatment of Crohn's disease and rheumatoid arthritis but with less certain results in limited trials. Informed readers are aware of the preliminary report showing short-term benefits of natalizumab for multiple sclerosis that appeared in the Journal in 2003.1 They are also mindful of the three cases of progressive multifocal leukoencephalopathy (PML) that were attributed to the drug,2,3,4 which led to its withdrawal from the market after four months, an unusually brief period of use.
Now a pivotal trio of articles in this issue of the Journal extend the efficacy of the drug to the two-year mark and provide reassurance that the risk of PML is small with relatively brief use.5,6,7 Beyond these findings, clinicians and patients are left wondering if and when natalizumab will be made available and what precautions might be taken to prevent the emergence of the JC virus, the causative agent of PML.
Clinical practice in multiple sclerosis is attentive to two pressing problems — namely, the prevention of acute demyelinating lesions and the forestalling of a transformation of the disease from the relapsing form to the chronic progressive form that causes the most serious disability. The presumption in clinical trials has been that control of the short-term biologic manifestations of disease, as measured by the number of acute relapses and of brain lesions detected by magnetic resonance imaging (MRI), will reduce neurologic damage. Furthermore, none of the drugs under discussion, including natalizumab, are unambiguously effective once the progressive phase of multiple sclerosis begins.
With this in mind, several points in the three Journal articles merit attention. The two-year Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) study5 of nearly 1000 patients indeed affirms that natalizumab has marked salutary biologic and clinical effects in multiple sclerosis. The annualized rate of clinical relapse was reduced by 68 percent (from 0.75 to 0.24), and the number of new or enlarging brain lesions on MRI was reduced by 83 percent. By way of perspective, the currently used drugs, interferon and glatiramer, diminish acute relapses by roughly one third. A further compelling result was the abatement of clinical progression (17 percent of patients receiving natalizumab had progression vs. 29 percent of those receiving placebo) and a similar prolongation of the interval before neurologic deterioration. It is tempting to project these improvements over a patient's lifetime, but there are no data yet to support such a view.
The two-year Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis (SENTINEL) trial6 of the combined administration of natalizumab and interferon reports a marked reduction in the rate of annualized relapse from 0.75 with interferon alone to 0.34 with dual treatment. The progression of disability showed a moderate reduction, from 29 percent with interferon alone to 23 percent with the addition of natalizumab. Although the two study populations were not identical, it is noteworthy that the rates of relapse and clinical progression with interferon in this trial and in the placebo group of the AFFIRM trial were nearly the same, emphasizing again the unimposing effects of the current generation of treatments.
It is reassuring that no further instances of PML were detected in either of these two large studies, but their duration of two years allows only limited inferences. The aforementioned cases of PML occurred after natalizumab had been given with interferon beta (or other immunosuppressive agents) for a period of 8 to 30 months. This dual immune suppression offered a plausible explanation for the emergence of latent JC virus, possibly vindicating natalizumab monotherapy. This point has not been settled.
In order to frame the risk of PML, Yousry and colleagues7 undertook an immense post facto surveillance program. Their methodology for identifying potential cases of PML among 3116 patients with multiple sclerosis, Crohn's disease, or rheumatoid arthritis in 11 trials was sound and probably would have detected most valid cases. However, 1700 patients in other trials were excluded, and scrutiny was purposely casual for some 7000 patients who received natalizumab commercially. The omissions concerning the latter group are surely of little concern since four or fewer doses had been given. (It bears emphasis that the huge number of treatments administered during only four months of open availability presumably reflected a vast unmet need of patients with multiple sclerosis.) An essential limitation of the survey was the average treatment of only 18 monthly doses (with a range of 8 to 37 months), a constraint that brackets any conclusions.
The authors of the PML survey fairly state, "We do not know the duration of exposure to natalizumab required to put patients at risk for PML." It seems that less than two years of treatment with natalizumab alone is relatively safe, but the possibility remains that PML will develop in 1 in 1000 patients. At the moment, it is doubtful that neurologists will chance using natalizumab in conjunction with other immunosuppressive agents, with the possible exception of corticosteroids when they are required for acute relapses.
The available data support the value of natalizumab as a potent treatment for multiple sclerosis in a new class of highly specific immune drugs. The convenience of a monthly infusion of natalizumab may hold more appeal for patients than weekly or more frequent self-injection of interferon and glatiramer. What clinical guidance is provided from these three studies would be enhanced by some method to predict which patients are at risk for PML and to determine during treatment if the JC virus has emerged from its latent state in the kidney. As suggested by previous editorialists, serial measurements of JC viral load could be used to interdict or to interrupt a course of natalizumab,8 but it is not yet clear if this is a practical solution. It seemed self-evident to everyone when these cases of PML were described that impeding lymphocyte traffic to the brain led to opportunistic viral entry. Ransohoff has speculated that natalizumab also acts on bone marrow cells to promote the mobilization of JC virus, thereby making the therapeutic effect of the drug inseparable from the risk of PML.9 If this theory is valid, investigators are challenged to design drugs that prevent sensitized T cells from entering the nervous system by mechanisms even more novel than those employed by natalizumab. Several of these drugs are already on the way.
Dr. Ropper reports having been the principal investigator for a multicenter trial of interferon for the treatment of peripheral neuropathy that was supported by a $15,000 grant from Biogen in February 2004. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Department of Neurology, Caritas St. Elizabeth's Medical Center, Boston.
References
Miller DH, Khan OA, Sheramata WA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003;348:15-23.
Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N Engl J Med 2005;353:362-368.
Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005;353:375-381.
Kleinschmidt-DeMasters BK, Tyler KL. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 2005;353:369-374.
Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;354:899-910.
Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006;354:911-923.
Yousry TA, Major EO, Ryschkewitsch C, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 2006;354:924-933.
Berger JR, Koralnik IJ. Progressive multifocal leukoencephalopathy and natalizumab -- unforeseen consequences. N Engl J Med 2005;353:414-416.
Ransohoff RM. Natalizumab and PML. Nat Neurosci 2005;8:1275-1275.(Allan H. Ropper, M.D.)
Now a pivotal trio of articles in this issue of the Journal extend the efficacy of the drug to the two-year mark and provide reassurance that the risk of PML is small with relatively brief use.5,6,7 Beyond these findings, clinicians and patients are left wondering if and when natalizumab will be made available and what precautions might be taken to prevent the emergence of the JC virus, the causative agent of PML.
Clinical practice in multiple sclerosis is attentive to two pressing problems — namely, the prevention of acute demyelinating lesions and the forestalling of a transformation of the disease from the relapsing form to the chronic progressive form that causes the most serious disability. The presumption in clinical trials has been that control of the short-term biologic manifestations of disease, as measured by the number of acute relapses and of brain lesions detected by magnetic resonance imaging (MRI), will reduce neurologic damage. Furthermore, none of the drugs under discussion, including natalizumab, are unambiguously effective once the progressive phase of multiple sclerosis begins.
With this in mind, several points in the three Journal articles merit attention. The two-year Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) study5 of nearly 1000 patients indeed affirms that natalizumab has marked salutary biologic and clinical effects in multiple sclerosis. The annualized rate of clinical relapse was reduced by 68 percent (from 0.75 to 0.24), and the number of new or enlarging brain lesions on MRI was reduced by 83 percent. By way of perspective, the currently used drugs, interferon and glatiramer, diminish acute relapses by roughly one third. A further compelling result was the abatement of clinical progression (17 percent of patients receiving natalizumab had progression vs. 29 percent of those receiving placebo) and a similar prolongation of the interval before neurologic deterioration. It is tempting to project these improvements over a patient's lifetime, but there are no data yet to support such a view.
The two-year Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis (SENTINEL) trial6 of the combined administration of natalizumab and interferon reports a marked reduction in the rate of annualized relapse from 0.75 with interferon alone to 0.34 with dual treatment. The progression of disability showed a moderate reduction, from 29 percent with interferon alone to 23 percent with the addition of natalizumab. Although the two study populations were not identical, it is noteworthy that the rates of relapse and clinical progression with interferon in this trial and in the placebo group of the AFFIRM trial were nearly the same, emphasizing again the unimposing effects of the current generation of treatments.
It is reassuring that no further instances of PML were detected in either of these two large studies, but their duration of two years allows only limited inferences. The aforementioned cases of PML occurred after natalizumab had been given with interferon beta (or other immunosuppressive agents) for a period of 8 to 30 months. This dual immune suppression offered a plausible explanation for the emergence of latent JC virus, possibly vindicating natalizumab monotherapy. This point has not been settled.
In order to frame the risk of PML, Yousry and colleagues7 undertook an immense post facto surveillance program. Their methodology for identifying potential cases of PML among 3116 patients with multiple sclerosis, Crohn's disease, or rheumatoid arthritis in 11 trials was sound and probably would have detected most valid cases. However, 1700 patients in other trials were excluded, and scrutiny was purposely casual for some 7000 patients who received natalizumab commercially. The omissions concerning the latter group are surely of little concern since four or fewer doses had been given. (It bears emphasis that the huge number of treatments administered during only four months of open availability presumably reflected a vast unmet need of patients with multiple sclerosis.) An essential limitation of the survey was the average treatment of only 18 monthly doses (with a range of 8 to 37 months), a constraint that brackets any conclusions.
The authors of the PML survey fairly state, "We do not know the duration of exposure to natalizumab required to put patients at risk for PML." It seems that less than two years of treatment with natalizumab alone is relatively safe, but the possibility remains that PML will develop in 1 in 1000 patients. At the moment, it is doubtful that neurologists will chance using natalizumab in conjunction with other immunosuppressive agents, with the possible exception of corticosteroids when they are required for acute relapses.
The available data support the value of natalizumab as a potent treatment for multiple sclerosis in a new class of highly specific immune drugs. The convenience of a monthly infusion of natalizumab may hold more appeal for patients than weekly or more frequent self-injection of interferon and glatiramer. What clinical guidance is provided from these three studies would be enhanced by some method to predict which patients are at risk for PML and to determine during treatment if the JC virus has emerged from its latent state in the kidney. As suggested by previous editorialists, serial measurements of JC viral load could be used to interdict or to interrupt a course of natalizumab,8 but it is not yet clear if this is a practical solution. It seemed self-evident to everyone when these cases of PML were described that impeding lymphocyte traffic to the brain led to opportunistic viral entry. Ransohoff has speculated that natalizumab also acts on bone marrow cells to promote the mobilization of JC virus, thereby making the therapeutic effect of the drug inseparable from the risk of PML.9 If this theory is valid, investigators are challenged to design drugs that prevent sensitized T cells from entering the nervous system by mechanisms even more novel than those employed by natalizumab. Several of these drugs are already on the way.
Dr. Ropper reports having been the principal investigator for a multicenter trial of interferon for the treatment of peripheral neuropathy that was supported by a $15,000 grant from Biogen in February 2004. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Department of Neurology, Caritas St. Elizabeth's Medical Center, Boston.
References
Miller DH, Khan OA, Sheramata WA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003;348:15-23.
Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N Engl J Med 2005;353:362-368.
Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005;353:375-381.
Kleinschmidt-DeMasters BK, Tyler KL. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 2005;353:369-374.
Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;354:899-910.
Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006;354:911-923.
Yousry TA, Major EO, Ryschkewitsch C, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 2006;354:924-933.
Berger JR, Koralnik IJ. Progressive multifocal leukoencephalopathy and natalizumab -- unforeseen consequences. N Engl J Med 2005;353:414-416.
Ransohoff RM. Natalizumab and PML. Nat Neurosci 2005;8:1275-1275.(Allan H. Ropper, M.D.)