Abstract
Multiple sclerosis (MS) is the commonest disabling neurological disease of young and middle-aged adults affecting 1 million persons world wide. The illness begins with a relapsing-remitting MS course in 85%–90% of patients; the other 10%–15% have a primary progressive onset MS. Our current understanding is that MS is an autoimmune disorder with an inflammatory T-cell attack on myelin or some component of the oligodendrocyte—myelin structure. Relapses of disease activity result in plaques of demyelination with destruction of myelin and, to a lesser, extent axons. Lymphocytes within the central nervous system tissue recruit more cells leading to an inflammatory cascade that causes myelin damage, axonal disruption, and neuronal death. If the plaque occurs in a vocal area of the central nervous system then symptoms relating to that area result. However, magnetic resonance imaging shows that ∼10 times more lesions occur in asymptomatic areas of the brain. Recovery from an initial relapse may appear relatively complete but persistent inflammation results in axonal injury and residual disability results. With time and accumulated lesion load, secondary degeneration of denuded axons results in the phase of secondary progressive MS usually 15–20 years after onset.
The Limitations of First Line Disease Modifying Therapies
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Natalizumab: Mode of Action
The adhesion molecule α4β1 integrin, expressed on the surface of all leukocytes except neutrophils, interacts with its receptor, vascular cell adhesion molecule-1, expressed on the vascular endothelial cell surface and mediates lymphocyte adhesion and migration in areas of inflammation (Lobb and Hemler 1994). Natalizumab, the first α4-integrin antagonist in the new class of selective adhesion molecule inhibitors, targets the α4-subunit of α4β1, blocking interactions with its cognate receptors, and reducing transmigration and leukocyte activation (Yednock and others 1992). In the brain parenchyma natalizumab blocks the interaction of α4β1 with ligands such as fibronectin and osteopontin.
Efficacy of Natalizumab in RRMS
The efficacy of natalizumab has been assessed in 2 randomized controlled trials. The AFFIRM study tested natalizumab as monotherapy and the SENTINEL study evaluated natalizumab as add-on therapy to IFNB-1a (Avonex). In AFFIRM, natalizumab monotherapy reduced the risk of sustained disability progression over 2 years by 42% and the rate of clinical relapses by 68% compared with placebo (Polman and others 2006). Natalizumab reduced the mean number of new or enlarging T2-hyperintense lesions by 83% and the mean number of Gd-positive lesions was reduced by 92%. In SENTINEL, natalizumab added to IFNB-1a reduced sustained disability progression by 24% and annualized relapse rate (ARR) by 55% over 2 years compared with IFNB-1a alone (Rudick and others 2006).
Postmarketing Clinical Experience with Natalizumab in RRMS
Natalizumab was approved by the U.S. Food and Drug Administration in November 2004 to reduce the frequency of clinical relapses in patients with relapsing forms of MS. In February 2005 dosing of natalizumab was suspended by the manufacturers when 3 cases of progressive multifocal leukoencephalopathy (PML) were identified (Kleinschmidt-DeMasters and Tyler 2005). Subsequently following intense review of all treated patients, natalizumab was once more made available to treat highly active RRMS patients (Goodin and others 2008). The manufacturer instigated observational programs in the United States and the rest of the world to assess the risks for PML and other potential opportunistic infections. In Europe the indications for the use of natalizumab in RRMS include (1) patients who have failed to respond to a full and adequate course of an IFNB—patients should have had at least 1 relapse in the previous year while on therapy, and have at least 9 T2-hyperintense lesions in brain magnetic resonance imaging (MRI) or at least 1 gadolinium-enhancing lesion; (2) patients with rapidly evolving severe RRMS—defined by 2 or more disabling relapses in 1 year, and with 1 or more gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI (EMEA Guidelines 2010).
The use of these guidelines in practice has been examined by German and Danish neurologists. In a German study of 31 patients treated with natalizumab because of suboptimal response to first-line therapies, the ARR for the year before natalizumab was 2.1, and that for the first year on natalizumab therapy was 0.2, a 90% reduction in the ARR (Putzki and others 2009). In the Danish nationwide study of 175 patients previously treated with a first-line DMT, the effect on the ARR was less marked; the ARR reduced to 0.71 in the first year of natalizumab therapy from a pretreatment rate of 2.71 (a 74% reduction) (Oturai and others 2009).
Opportunistic Infections Associated with Natalizumab Therapy
Progressive multifocal leukoencephalopathy
Thirty-five cases of PML have been reported in patients with MS to February 2010. The overall risk for PML is estimated as being 1/1,000 patients treated; however, it seems that the risk may increase in patients treated for >2 years and in patients previously treated with other immunosuppressants, notably mitoxantrone. The number of patients treated for >3 years is relatively small and accurate risk figures (without wide confidence limits) are lacking. The management of this risk is a great problem for neurologists and their patients with highly active MS (Major 2009). At present the use of clinical vigilance remains the only way to detect PML; measures such as the presence of JCV viruria, JCV viraemia, and JCV antibody titres are of no prognostic significance. If PML is suspected in any patient, then MRI brain may strengthen the suspicion; cerebrospinal fluid examination for the detection of the JCV is required as the ultimate diagnostic test (Yousry and others 2006). PML in the MS patient on natalizumab is treated by stopping further infusions and by plasma exchange to remove any circulating unbound natalizumab (Khatri and others 2009). Several weeks later an immune reconstitution syndrome develops and is treated with high-dose intravenous steroids; increased neurological deficits and death may result (Wenning and others 2009). Other opportunistic infections reported with natalizumab include cryptosporidial gastroenteritis, pneumocystis carinii pneumonia, varicella pneumonia, and mycobacterium avium intracellulare complex pneumonia.
Summary
Natalizumab is an extremely effective therapy for highly active RRMS. The risk for PML and other opportunistic infections remains relatively small, but requires rigorous on-going clinical surveillance. The advent of oral therapies, cladribine, and fingolimod currently awaiting approval, and other therapies under trial, including alemtuzumab, may prove to be viable alternatives to natalizumab. For the present, natalizumab remains a very useful tool for treating RRMS patients who show poor response to first line DMTs.
Footnotes
Author Disclosure Statement
M. Hutchinson served on the medical advisory board for the AFFIRM study for Biogen-Idec and serves on a medical advisory board (BG00012) for Biogen-Idec. He is on the editorial boards of the Multiple Sclerosis journal and the International MS journal and receives research support from Dystonia Ireland.