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Disclosures: Michael J Olek, DO Nothing to disclose. Francisco Gonzalez-Scarano, MD Employment: University of Texas Health Science Center, San Antonio; University of Pennsylvania. Equity Ownership/Stock Options: Multiple, but traded by advisors without my input (Pharmaceutical). Other Financial Interests: NeuroLink (Venture Capital). John F Dashe, MD, PhD Employee of UpToDate, Inc.
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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).
●In the AFFIRM trial, 942 patients with relapsing MS were randomly assigned to receive either monotherapy with natalizumab 300 mg (n = 627), or placebo (n = 315) by intravenous infusion every four weeks for two years . Natalizumab treatment was associated with a statistically significant 68 percent reduction in annualized relapse rate compared with placebo treatment at one year (0.26 versus 0.81), a reduction that was maintained at two years, and with a significant reduction in the cumulative probability of sustained disability progression at two years (17 versus 29 percent).
●In the SENTINEL trial, 1171 patients with relapsing MS who continued to experience disease activity despite interferon beta-1a treatment were randomly assigned to also receive natalizumab 300 mg (n = 589) or placebo (n = 582) by intravenous infusion every four weeks . All patients continued to receive interferon beta-1a throughout the trial. The study was stopped about one month early because two patients developed progressive multifocal leukoencephalopathy (see 'Risk of progressive multifocal leukoencephalopathy' below). Combination therapy (natalizumab plus interferon beta-1a) was associated with a statistically significant 54 percent reduction in annualized relapse rate compared with placebo at one year (0.38 versus 0.82), a difference that was maintained at two years, and with a significant reduction in the risk of sustained disability progression at two years (23 versus 29 percent).
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 August 2013, 398 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: Treatment and prognosis", section on 'Natalizumab-associated PML'.)
●Previous infection with JC virus as suggested by baseline seropositivity for anti-JC virus antibodies
●Prior immunosuppressant treatment
●Duration of natalizumab exposure
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:
●In patients who were seronegative at baseline for anti-JC virus antibodies, the estimated risk of natalizumab-associated PML was ≤0.09 per 1000 (95% CI 0.0-0.48) . This analysis assumed that PML developed in one hypothetical patient negative for anti-JC virus antibodies at baseline, a reasonable assumption since the false negative rate of the anti-JC virus antibody assay is approximately 3 percent.
●For patients who were seropositive for anti-JC virus antibodies but had no prior exposure to immunosuppressant treatment, the estimated risk of PML with 1 to 24 months of natalizumab treatment was 0.56 per 1000 patients (95% CI 0.36–0.83) and for 25 to 48 months of treatment was 4.6 per 1000 (95% CI 3.7–5.6) .
●For patients who were both seropositive for anti-JC virus antibodies and had previous immunosuppressant treatment (eg, azathioprine, cyclophosphamide, methotrexate, mitoxantrone, mycophenolate, or a combination), the estimated PML risk with 1 to 24 months of natalizumab treatment was 1.6 per 1000 patients (95% CI 0.9-2.6) and the estimated risk for 25 to 48 months of treatment was 11.1 per 1000 (95% CI 8.3-14.5) .
These data confirm that natalizumab, even as monotherapy, is a risk factor for PML [21,22]. 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 [24,25].
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:
●Natalizumab treatment may increase the risk of melanoma in patients with atypical moles, ocular nevi, or a family history of melanoma. This hypothesis is based upon a report of two women with MS who had long-standing nevi and subsequently developed melanoma in close temporal relationship with the start of natalizumab therapy .
●Clinically significant liver injury has been observed in a few patients taking natalizumab [27,28]. Signs of hepatic injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, occurred as early as six days after the first dose of natalizumab. Therefore, natalizumab should be discontinued in patients with jaundice or other evidence of significant liver injury.
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 [33,34]. 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: Treatment and prognosis", 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.
●The largest study followed over 1800 patients with MS who were enrolled in the controlled trials of natalizumab when the trials were suspended and the drug was temporarily withdrawn from the market due to the detection of initial cases of PML . Disease activity began to increase soon after cessation of natalizumab and reached pre-natalizumab levels by four to seven months. In patients with highly active MS, the ARR increased from 0.27 on-treatment to 1.56 at four months after natalizumab discontinuation. Of importance, the level of MS disease activity during the eight month period of natalizumab treatment interruption never exceeds the levels observed in patients who were assigned to placebo in the clinical trials.
●In a prospective study of 23 patients with MS, there was no significant difference in neurologic disability for the patient cohort before, during, and 14 months after discontinuation of natalizumab . Most patients were treated with another disease-modifying drug after stopping natalizumab.
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 [39-42]. The following reports illustrate this issue:
●In the largest published report, which evaluated patients with MS who were treated with 12 or more natalizumab infusions, clinical relapse within six months of natalizumab suspension occurred in 19 of 68 patients (28 percent) at a median of three months from treatment suspension, compared with none of 16 patients during months 12 to 18 of ongoing natalizumab treatment; the difference was statistically significant . Among the 19 patients with clinical relapse, seven had a severe flare, with an increase on the Expanded Disability Status Scale from a median of 3.0 to 6.0 and the development of multiple new enhancing lesions on brain MRI (mean 16, range 6 to 40). Only four patients in the study were treated with another disease-modifying agent after discontinuing natalizumab, and none had a relapse.
●In another study of patients who had received 12 or more consecutive months of natalizumab therapy, relapses occurred after mean natalizumab interruption of approximately four months in nine of 24 patients (38 percent) with relapsing-remitting MS and in two of eight patients with secondary progressive MS (SPMS) . A third patient with SPMS experienced two severe relapses shortly after restarting natalizumab. In several patients, particularly those with SPMS, the relapses were considered unusually severe with widespread gadolinium lesion enhancement on MRI involving areas of previous demyelination. The mean number of gadolinium-enhancing MRI lesions that occurred after natalizumab discontinuation was significantly greater than the mean number of such lesions observed during attacks prior to starting natalizumab (9.5 versus 2.6). During the period of natalizumab interruption, none of the patients were treated with another disease-modifying therapy.
●In a series of 10 clinically stable patients with MS who discontinued natalizumab after 12 to 40 months of therapy, clinical relapse and/or new lesions on MRI within six months of treatment interruption on MRI occurred in seven patients .
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.)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Basics topics (see "Patient information: Multiple sclerosis in adults (The Basics)")
SUMMARY AND RECOMMENDATIONS
●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.
•The reduction in the annualized relapse rate for RRMS seen with natalizumab therapy in randomized trials (54 to 68 percent) compares favorably to the reduction seen with interferon beta drugs or glatiramer acetate treatment in other randomized trials (about 33 percent). However, there are no randomized trials comparing natalizumab directly with other disease modifying agents. Thus, the relative effectiveness of natalizumab for RRMS compared with current disease modifying agents cannot be defined accurately. (See 'Effectiveness' above.)
•The overall risk of PML with natalizumab therapy is estimated to be approximately 2.1 in 1000. The risk of PML is increased with the duration of natalizumab therapy, prior immunosuppressant treatment, and seropositivity for anti-JC virus antibodies prior to natalizumab treatment (table 1). For patients who are seronegative for JC virus and have no prior history of immunosuppression, the risk of PML in the first 24 months of natalizumab therapy is very low. (See 'Risk of progressive multifocal leukoencephalopathy' above and 'PML risk stratification' above.)
●For patients with highly active RRMS who have a poor response to both beta interferons and glatiramer acetate, or intolerance of these immunomodulators, we suggest treatment with natalizumab (Grade 2B). However, some experts routinely use natalizumab early in the course of RRMS. Natalizumab is approved for use as monotherapy only. (See 'Clinical use' above.)
●Patients receiving natalizumab must be followed in a risk management program to monitor for symptoms or signs suggestive of progressive multifocal leukoencephalopathy. (See 'Risk management program' above.)
●Because of the risk of PML, some MS centers employ a three or four month suspension (ie, a drug holiday) of natalizumab after one year of treatment in order to restore immune surveillance. 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. For patients with MS who are being treated with natalizumab because of a high pretreatment MS disease activity level, we suggest not employing a drug holiday (Grade 2C). However, a natalizumab drug holiday is a reasonable option for patients who are more concerned about the risk of developing PML than the risk of increased MS disease activity. (See 'Drug holiday' above.)
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