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INTRODUCTION — Natalizumab is an effective drug for the treatment of relapsing-remitting multiple sclerosis (RRMS). However, its use is rarely associated with the development of progressive multifocal leukoencephalopathy (PML), a potentially fatal complication.
This topic will review the use of natalizumab for the treatment of refractory or aggressive RRMS in adults. For initial disease modifying therapy of relapsing-remitting multiple sclerosis (RRMS), it is reasonable to begin treatment with interferon beta-1a, interferon beta-1b, or glatiramer acetate. These agents are discussed in detail separately. (See "Treatment of relapsing-remitting multiple sclerosis in adults".)
BACKGROUND — Natalizumab is a recombinant monoclonal antibody directed against alpha-4 integrins. The formation of inflammatory lesions in patients with MS may involve lymphocytes and monocytes that gain access to the brain parenchyma from the circulation by first adhering to vascular endothelial cells [1,2]. Alpha-4 integrin is expressed on the surface of inflammatory lymphocytes and monocytes and may play a critical role in their adhesion to the vascular endothelium.
Treatment with alpha-4 integrin antagonists in rodent models of MS led to reduced signs of disease activity and inflammation [3-5]. In a preliminary six month clinical trial of 213 patients with MS, natalizumab treatment was associated with significantly fewer new enhancing brain lesions on MRI and significantly fewer relapses compared with placebo . In patients with MS, natalizumab treatment is associated with a diminished migratory capacity of immune cells and a prolonged decrease in lymphocyte counts in the cerebrospinal fluid [7,8].
EFFECTIVENESS — In a 2011 systematic review of trials evaluating natalizumab for relapsing forms of MS, pooled efficacy data from two randomized controlled trials – AFFIRM and SENTINEL – showed that natalizumab significantly reduced the risk for having a relapse during two years of treatment (relative risk [RR] 0.57, 95% CI 0.47 to 0.69) . In addition, natalizumab significantly reduced the risk for experiencing progression at two years (RR 0.74, 95% CI 0.62-0.89). The number needed to treat (NNT) to prevent one new exacerbation at two years was 4 (95% CI 3-5) and the NNT to prevent progression at two years was 10 (95% CI 7-23).
Natalizumab was beneficial in all analyses of primary and secondary endpoints in both the AFFIRM and SENTINEL trials, indicating the robust nature of the results [10,11]. As an example, natalizumab treatment as monotherapy (in AFFIRM) or combination therapy (in SENTINEL) was associated with an 83 percent reduction in the number of new or enlarging hyperintense lesions on T2-weighted MRI. Finally, natalizumab treatment was associated with improved health-related quality of life compared with placebo .
The reduction in the annualized relapse rate seen with natalizumab in these trials (54 to 68 percent) compares favorably to the reduction seen with interferon beta or glatiramer acetate treatment in clinical trials (about 33 percent) . However, indirect comparisons of effectiveness across trials do not provide compelling evidence of an advantage for natalizumab, and there are no randomized trials comparing natalizumab directly with other disease modifying agents. In the absence of such trials, the 2008 AAN guidelines concluded that the relative effectiveness of natalizumab compared with current disease modifying agents cannot be defined accurately .
RISK OF PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY — Natalizumab treatment is associated with a risk of developing progressive multifocal leukoencephalopathy (PML), a rare potentially fatal neurologic disease caused by reactivation of JC virus infection. (See "Progressive multifocal leukoencephalopathy: Epidemiology, clinical manifestations, and diagnosis", section on 'Epidemiology'.)
Historically, natalizumab was withdrawn from the market in early 2005 after two patients receiving the drug to treat MS developed confirmed PML, which was the cause of death in one [15-17]. PML was also reported in a patient treated with natalizumab for Crohn's disease. A relationship between natalizumab therapy and the onset of PML was supported by the detection — after initiation of natalizumab therapy — of a new and rising JC viral load in serum that preceded the onset of neurologic symptoms [15,18]. Natalizumab was reintroduced to the US and European markets in mid 2006 for use only as monotherapy to treat relapsing forms of MS. Thereafter additional cases of PML associated with natalizumab therapy began to emerge. By February 2012, 212 cases of PML associated with natalizumab therapy had been reported worldwide .
Empiric treatment of PML associated with natalizumab therapy is discussed separately. (See "Progressive multifocal leukoencephalopathy: Prognosis and treatment", section on 'Natalizumab-associated PML'.)
A 2012 review of natalizumab-associated PML in patients with MS evaluated data from three clinical trials and a registry of patients with MS . For patients treated with natalizumab for MS, the overall estimated incidence of PML was 2.1 per 1000 patients (95% CI 1.9-2.4). However, among 54 patients with available serum samples who developed natalizumab-related PML, the seropositive rate for anti-JC virus antibodies prior to the diagnosis of PML was 100 percent . In contrast, among all 5896 patients with MS who were enrolled in the controlled trials and registries, the seropositive rate for anti-JC virus antibodies was approximately 55 percent. These data and information about prior immunosuppressant treatment were used to refine the estimates for the risk of natalizumab-associated PML as follows:
These data confirm that natalizumab, even as monotherapy, is a risk factor for PML [19,21]. In addition, they suggest that previous immunosuppressant treatment increases the risk of natalizumab-associated PML by three- to four-fold, and that the highest risk is seen in patients who are seropositive for anti-JC virus antibodies at baseline, have prior immunosuppressant treatment, and received natalizumab for more than 24 months.
In contrast to JC virus antibodies, testing for JC virus DNA in blood or urine appears to have no utility for determining the risk of PML. Although a small early study suggested that subclinical reactivation of JC virus was frequent in patients treated with natalizumab for MS , this was not confirmed in larger investigations [23,24].
OTHER SIDE EFFECTS — In two large, randomized, controlled trials, adverse events associated with natalizumab treatment (other than progressive multifocal leukoencephalopathy) included fatigue, allergic reactions, anxiety, pharyngitis, sinus congestion, and peripheral edema [10,11]. Natalizumab should be discontinued in patients who develop hypersensitivity reactions.
Other potential side effects have been reported in small numbers of patients:
Antibodies to natalizumab — Antibodies to natalizumab developed in approximately 9 percent of patients in the AFFIRM and SENTINEL trials, and these antibodies were persistently positive in about 6 percent . When compared with antibody negativity, persistent anti-natalizumab antibody positivity was associated with reduced clinical effectiveness of natalizumab treatment (as measured by disability progression, relapse rate, and MRI lesion formation) and with an increased incidence of infusion reactions.
The authors of the study suggest testing for antibodies after six months of natalizumab therapy in patients who have continued clinical MS activity or persistent infusion reactions, and stopping natalizumab if antibody positivity is confirmed by retesting after three more months .
CLINICAL USE — Guidelines published in 2008 by the American Academy of Neurology (AAN) recommend that natalizumab be reserved for the treatment of selected patients with RRMS who have failed other therapies because of continued disease activity or medication intolerance, or who have a very aggressive initial disease course . The guidelines also recommend that natalizumab not be used in combination with beta interferons because the combination may increase the risk of progressive multifocal leukoencephalopathy. Furthermore, the AAN recommends that the combination of natalizumab with agents that do not induce immune suppression should be reserved for clinical trials.
Given the data regarding its effectiveness and side effects, particularly the risk of progressive multifocal leukoencephalopathy, we are in general agreement with the AAN guidelines and recommend that natalizumab should be reserved for patients with active RRMS that is refractory or resistant to beta interferons and glatiramer acetate, and for patients who are intolerant of these medications . (See "Treatment of relapsing-remitting multiple sclerosis in adults", section on 'Refractory disease'.)
However, some experts believe that natalizumab is more effective than any other available MS disease modifying treatment and therefore routinely use it early in the course of RRMS, rather than reserving only it for patients who have a high level of early disease activity or for those who are refractory to other agents.
Natalizumab treatment should not be used in patients who may have impaired immunity [32,33]. We suggest stopping glucocorticoids and other immunomodulators for at least one month prior to starting natalizumab. A longer wash-out period (up to three months or more) is suggested for azathioprine, methotrexate, mycophenolate, mitoxantrone, and cyclophosphamide . Leukocyte and neutrophil counts should be within or close to the normal range. Natalizumab is contraindicated in patients who have hematologic or rheumatologic conditions associated with compromised cell-mediated immunity.
A brain MRI scan should be obtained prior to initiating therapy with natalizumab.
Risk management program — The reintroduction of natalizumab is accompanied by a risk management program (the TOUCH program) that requires enrollment by prescribers as well as 12 specialty pharmacies and approximately 4500 infusion centers that dispense the drug in the United States . Clinicians must evaluate patients at three and six months after natalizumab treatment is started, and every six months thereafter. Patients receiving natalizumab will enroll in a mandatory registry and complete a checklist that inquires about medications and new symptoms suggestive of progressive multifocal leukoencephalopathy (PML) prior to monthly infusions.
Rigorous follow-up is essential in order to detect the onset of symptoms and signs related to PML as opposed to those related to MS . In general, MS relapses are characterized by acute onset, typically occurring over hours to days, with eventual stabilization and resolution, and typical presentations that include diplopia, optic neuritis, and myelopathy. In contrast, PML is characterized by subacute onset over several weeks, progressive disease, and presentations that include aphasia, behavioral and neuropsychiatric abnormalities, cortical visual deficits, hemiparesis, and seizures.
When there is suspicion for PML, natalizumab should be discontinued . The management of natalizumab-related PML is discussed elsewhere. (See "Progressive multifocal leukoencephalopathy: Prognosis and treatment", section on 'Natalizumab-associated PML'.)
Drug holiday — Some MS centers employ a three or four month suspension of natalizumab after one year of treatment in order to restore immune surveillance. The rational for doing so is that the risk of progressive multifocal encephalopathy (PML) is believed to be dependent on both the cumulative dose and duration of natalizumab therapy. (See 'Risk of progressive multifocal leukoencephalopathy' above.)
One concern with this strategy is the possibility that stopping natalizumab may lead to a sudden worsening or rebound of MS disease activity, with rebound defined by an increase in the either the rate or severity of relapses compared with pretreatment disease activity. However, the bulk of the available evidence, though uncontrolled, suggests that disease activity returns to levels similar to pretreatment levels and tends to peak about four months after natalizumab is discontinued . Additionally, the increase in disease activity is greater for patients with higher pretreatment disease activity, and does not appear to exceed the levels seen in patients randomly assigned to placebo.
Other studies, though limited by small patient numbers, have nevertheless raised concern that a rebound effect or a more severe reaction similar to the immune reconstitution inflammatory syndrome may follow discontinuation of natalizumab [38-41]. The following reports illustrate this issue:
Although definitive evidence is lacking, we conclude that a drug holiday of three to four months is unlikely to cause MS rebound but may lead to a return of MS disease activity to the level that was present before natalizumab treatment. Therefore, we suggest it should not be done routinely, particularly for patients with highly active MS prior to starting natalizumab. However, patient preferences must be considered, and a drug holiday of three to four months after one year of natalizumab treatment is a reasonable option for patients who are more concerned about the risk of developing PML than the risk of increased MS disease activity. For such patients, we suggest treatment with another disease-modifying agent or monthly glucocorticoids for the duration of the natalizumab drug holiday. (See "Treatment of relapsing-remitting multiple sclerosis in adults".)
Patients with MS who have antibodies to the JC virus are at increased risk of developing PML compared with those who do not have such antibodies. Thus, the results of JV virus antibody testing could influence the decision for individual patients regarding the need for natalizumab drug holidays. (See 'PML risk stratification' above.)
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