Multiple Sclerosis Research: Diagnostics, Disease-Modifying

S14 Journal of Neuroscience Nursing Multiple Sclerosis Research: Diagnostics, Disease-Modifying Treatments, and Emerging Therapies Kathleen Costello ABSTRACT Multiple sclerosis (MS) is a complex disease that affects the central nervous system. It is believed to be an immune mediated disease, and although the etiology remains unknown, it is believed to occur from a combination of genetic risk factors and environmental risk factors. There is no single diagnostic test for MS, and diagnostic criteria have been developed to aid the provider in making an accurate and timely diagnosis. Once a diagnosis of MS is made, treatments directed toward the inflammatory immune response should be initiated. Currently, there are 10 treatments for MS: four interferon beta products; one glatiramer acetate; one monoclonal antibodyVnatalizumab; three oral treatmentsVfingolimod, teriflunomide, and dimethyl fumarate; and one immunosuppressant agentVmitoxantrone. Each of these agents has a different administration and different risks and side effects. Numerous agents are in late stage development, and it is possible that several more agents, all with different mechanisms of action, will become available over the next several years.

Keywords: alemtuzumab, daclizumab, dimethyl fumarate, disease modifying treatment, fingolimod, glatiramer acetate, interferon beta, laquinimod, MCDONALD Criteria, multiple sclerosis, natalizumab, teriflunomide

ultiple sclerosis (MS) is a chronic disease of the disease from onset, known as primary progres- of the central nervous system (CNS) path- sive MS (Lublin & Reingold, 1996). Mologically characterized by CNS inflam- The etiology of MS is unknown; however, it is mation, demyelination, and axonal loss (Compston thought to be because of a complex interplay of fac- & Coles, 2008). Clinically, the disease is most often tors including genetic risk for autoimmunity, immune characterized by early relapses and remissions of system dysregulation, and environmental factors (i.e., neurological symptoms referable to the CNS, a clin- viral exposure, particularly Epstein Barr, vitamin D ical course known as relapsing-remitting MS (RRMS). deficiency, and smoking; Ascherio & Munger, 2007; After early relapses with characteristic inflammation Giovannoni & Ebers, 2007; Shirani & Tremlett, 2010). and demyelination, there is some functional reorga- Immunologically, the inflammatory process is thought nization and remyelination that occurs early in the to be mediated by T-cell and B-cell responses to CNS disease and helps to restore function. Over time, RRMS autoantigens. The inflammation that occurs within the often transitions to a disease course characterized by a CNS is also responsible, at least in part, for degen- progressive decline in function. Although relapses may erative changes, including axonal loss and damage to still occur, they occur less often; this course of MS is oligodendrocytes that lead to irreversible damage in known as secondary progressive MS. In individuals the brain and spinal cord. with secondary progressive MS, early repair mecha- Symptoms of MS vary widely in type and severity. nisms fail and more axonal loss occurs (Hagemeier, Common symptoms include generalized and fre- Bruck, & Kuhlmann, 2012). Approximately 10%Y15% quently overwhelming fatigue; depression; unilateral of all patients with MS will have a progressive course visual blurring or loss; diplopia; sensory symptoms, such as numbness, tingling, or pain; incoordination; spasticity; weakness; ataxia; and elimination dysfunction, Questions or comments about this article may be directed to such as urgency, frequency, and incontinence of bladder Kathleen Costello, MS RN ANP-BC MSCN MSCS, at kcostel5@ or bowel. Cognitive impairment, such as short-term jhmi.edu. She is a Nurse Practitioner at Johns Hopkins Multiple Sclerosis Center, Baltimore, MD. memory loss and slowed processing, is also possible. Conflicts of interest and source of funding: Kathleen Costello has served on Scientific Advisory Boards for Teva Neuroscience, Diagnostics Genzyme, Sanofi, Aventis, BiogenIDEC, EMDSerono, Questcor, Making the diagnosis of MS can be quite chal- and Novartis Pharmaceuticals. lenging because there is no specific diagnostic test. Copyright B 2013 American Association of Neuroscience Nurses Traditionally, the diagnosis is made if there are at

Copyright © 2013 American Association of Neuroscience Nurses. Unauthorized reproduction of this article is prohibited. Supplement to: Volume 45 & Number 6S & December 2013 S15 least two neurological events referable to the CNS, separated or disseminated in space (different areas In the past 10-plus years, the of the CNS) and time (events occur at different points in time), with objective evidence of CNS involvement diagnostic ‘‘standard’’ known as the and all other possible causes of the symptoms are excluded. The diagnosis is mostly based on history of McDonald criteria has been neurological symptoms and neurological examination revised twice to reflect the findings. More recently, magnetic resonance imaging (MRI) findings and other paraclinical testing, such increased evidence of MRI changes as spinal fluid analysis, have been used to establish consistent with MS. dissemination in space and time when two clinical events have not occurred but MS is believed to be the most likely diagnosis. Since the mid-1960s, there have been published MRI and/or cerebrospinal fluid abnormalities to es- diagnostic criteria developed by MS experts that have tablish dissemination in space and/or time when only helped with the diagnosis of MS. In 2001, an inter- a single clinical event has occurred. Imaging criteria national panel of MS experts convened and developed for the 2010 McDonald criteria revision were based criteria that utilized both clinical and MRI findings, on recent publications from the MAGNIMS research including the criteria of dissemination in space and group (Montalban et al., 2010; Rovira et al., 2009; time (McDonald et al., 2001). Since 2001, these cri- Swanton et al., 2007). Fluid-attenuated inversion recov- teria, known as the McDonald criteria, have been ery and T2-weighted sequences are the MRI tech- revised, both in 2005 (Polman et al., 2005) and in 2010 niques that are currently of greatest clinical interest in (Polman et al., 2011). In each of the revisions, the MS, along with postcontrast T1-weighted scans. These MRI criteria have been modified to reflect increased sequences provide information about active inflamma- evidence of MRI changes consistent with MS. tory and subclinical MS activity. Subclinical activity One of the goals of these criteria is to expedite the occurs much more frequently than do clinical symp- diagnosis of MS. Therefore, the McDonald diagnostic toms (Filippi et al., 2011). criteria have traditionally been applied to those indi- On the basis of the McDonald criteria, the criterion viduals who present with a clinically isolated syn- for dissemination in space can be met by the presence drome (CIS). The CIS is a term that describes the first of an MRI lesion in at least two of four areas of the onset of neurological symptoms in an individual, which CNS, which include juxtacortical, periventricular, in- usually involve the optic nerve, brainstem, or spinal fratentorial, or spinal cord (Figure 1). The criterion of cord and are characteristic of MS (Miller et al., 2008). dissemination in time can be met with an additional Symptoms should last a minimum of 24 hours in the T2 lesion and/or gadolinium (Gd)-enhancing lesion absence of infection. Individuals who have symptoms on a subsequent MRI, performed at any time after the and an MRI suggestive of inflammation and demye- initial MRI, or the simultaneous presence of asymp- lination or spinal fluid with findings consistent with tomatic Gd-enhancing lesions and nonenhancing le- MS are considered at high risk to develop additional sions in an individual with CIS (Polman et al., 2011). symptoms and would then be considered to have MS. If the criteria for dissemination in space and time are The diagnostic criteria utilize paraclinical evidence of met in the absence of additional clinical symptoms

FIGURE 1 MRI in Multiple Sclerosis

and other causes of the symptoms have been com- the interaction of free water protons and bound protons pletely excluded, the diagnosis of MS can be made and provides information about areas of MS damage (Polman et al., 2011). Other possible causes of neu- as well as normal-appearing white matter (Filippi & rological symptoms that must be excluded include Rocca, 2007). MR spectroscopy provides quantifica- other inflammatory conditions, CNS infections, met- tion of chemical changes found in lesions and normal- abolic conditions, vascular conditions, and inherited appearing white matter. Considered a marker of axonal conditions. Table 1 lists some of the diagnostic mimics integrity, N-acetyl aspartate can be measured using of MS. MR spectroscopy and provides evidence of the ex- Although not part of the MRI diagnostic criteria tent of axonal damage (Poloni, Minagar, Haacke, & nor part of the conventional imaging of clinical prac- Zivadinov, 2011). tice, nonconventional imaging techniques have been Optical coherence tomography (OCT), a non-MRI utilized to identify additional CNS pathology in MS. imaging tool, is a noninvasive method to observe and These techniques have added to the overall understand- quantify the retinal nerve fiber layer thickness. The ing of the disease. Although traditionally thought to retinal nerve is unmyelinated; thus, OCT is able to be a white matter disease, gray matter abnormalities quantify axonal integrity and damage. Gordon-Lipkin have been identified through the use of high-field-strength and colleagues showed that OCT correlated with brain MRI (Stadelmann, Albert, Wegner, & Bruck, 2008). atrophy in MS (Gordon-Lipkin et al., 2007). This im- Calabrese and colleagues examined 59 patients with aging tool may be an important outcome measure- CIS and showed that gray matter atrophy in the su- ment in clinical trials of neuroprotection because it perior frontal gyrus, thalamus, and cerebellum were provides information about axonal integrity. independent predictors of conversion from CIS to MS (Calabrese et al., 2011). In addition, gray matter atrophy DMTs in patients with MS is associated with progression of Once the diagnosis of CIS or MS is made, treatment MS (Fisniku et al., 2008). can be considered. DMTs, available since the early Imaging techniques, such as brain parenchymal 1990s, are able to alter the natural history of RRMS fraction and structural image evaluation using normal- because of their anti-inflammatory effect on the im- ization of atrophy, provide different methods to quan- mune system. These agents have shown efficacy in the tify brain atrophy. These techniques have shown reduction of relapse frequency and reduction in CNS that brain atrophy measurements correlate better with inflammation and have a variable ability to reduce disability than do conventional MRI techniques. It the progression of disability. Emerging treatments in has been suggested that atrophy measurements may the research pipeline promise alternate mechanisms of be a useful way of measuring the ability of disease- action from the currently approved treatments as well modifying treatments (DMTs) to provide neuroprotec- as efficacy in relapse reduction, inflammatory events, tion (Barkhof, Calabresi, Miller, & Reingold, 2009). and progression of disability. Other MRI techniques utilized in the research arena Currently, there are 10 Food and Drug Adminis- are magnetic transfer imaging (MT-MRI) and MR tration (FDA)-approved treatments for MS, including spectroscopy. MT-MRI is a technique that measures four interferon beta preparations, glatiramer acetate,

TABLE 1. MS Mimics (Cohen & Rensel, 2000) Inflammatory Infections Metabolic Vascular Inherited Lupus erythematosus Lyme disease Vitamin B12 deficiency Migraine CADISIL Sarcoidosis HTLV-1 Hypothyroidism Antiphospholipid Cerebellar-pontine syndrome degeneration Sjo¨ gren HIV Copper deficiency Diabetes Leukodystrophy Rheumatoid arthritis Neurosyphilis Elevated zinc ADEM Transverse myelitis Behc¸et disease Neuromyelitis optica

Note. MS = multiple sclerosis; CADISIL = cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; HTLV-1 = human T-lymphotropic virus type 1; HIV = human immunodeficiency virus; ADEM = acute disseminated encephalomyelitis.

Copyright © 2013 American Association of Neuroscience Nurses. Unauthorized reproduction of this article is prohibited. Supplement to: Volume 45 & Number 6S & December 2013 S17 natalizumab, fingolimod, mitoxantrone, teriflunomide, by provoking the immune system to shift to a less and dimethyl fumarate (DMF; Table 2). The interfer- inflammatory response. In several clinical trials, glatiramer ons, glatiramer acetate, natalizumab, teriflunomide, acetate has shown a favorable effect on relapses and fingolimod, and DMF are indicated for RRMS. MRI outcomes. An open-label extension of the orig- Mitoxantrone is indicated for secondary progressive inal phase 3 trial is ongoing and has established the MS, worsening relapsing MS, and progressive re- long-term safety of glatiramer acetate (Ford et al., 2010). lapsing MS. In well-designed clinical trials, the in- More recent additions to the MS treatment arma- terferon preparations and glatiramer acetate have mentarium are natalizumab, fingolimod, teriflunomide, been shown to delay the conversion of CIS to MS and DMF. Natalizumab is indicated for RRMS and is (Comi et al., 2009, 2012a; Jacobs et al., 2000; Kappos recommended in patients who have had a suboptimal et al., 2006a). Two separate head-to-head trials showed response to injectable treatments or cannot tolerate superiority in reducing relapses and improving MRI other treatments. Natalizumab blocks VLA-4, an outcomes for high-dose/high-frequency interferon adhesion molecule found on activated lymphocytes. beta compared with weekly interferon beta-1a (Durelli Without adhesion to the blood vessel wall, activated et al., 2002; Panitch et al., 2005). Two other separate lymphocytes are unable to traffic into the CNS. head-to-head trials of interferon beta and glatiramer Natalizumab was studied in two large clinical trials acetate showed a similar effect on relapse outcomes and, in both, was shown to have a statistically signifi- (Mikol et al., 2008; O’Connor et al., 2009). cant effect on relapses, disability progression, and MRI Unfortunately, in secondary progressive MS and outcomes (Polman et al., 2006; Rudick et al., 2006). primary progressive MS, the clinical trial results of Natalizumab is associated with progressive multifocal the available agents were not as positive. Only the leukoencephalopathy (PML), a rare infection of the European trial of interferon beta-1b showed a favor- CNS caused by the John Cunningham virus (JCV). able effect on progression in secondary progressive JCV infects approximately one half of the adult pop- MS (PRISMS [Prevention of Relapses and Disability ulation and, as a primary infection, is not associated by Interferon beta-1a Subcutaneously in Multiple Scle- with clinical symptoms. The virus becomes latent after rosis] Study Group, 1998). The North American trial the initial exposure and can become reactivated under of interferon beta-1b in secondary progressive MS certain conditions, such as untreated human immuno- was unable to corroborate those results (Panitch et al., deficiency virus, immunosuppressant treatment, and 2004). Upon further evaluation of the two trials, it was treatment with certain monoclonal antibodies, includ- apparent that the populations studied in the two trials ing rituximab and natalizumab. Reactivated JCV can were slightly different, with the European cohort having infect the CNS and causes widespread damage to more inflammatory activity (Derwenskus, 2011). A myelin and oligodendrocytes, ultimately resulting in study of glatiramer acetate in primary progressive MS death if the causative agent is not promptly removed was stopped after the interim analysis showed that the or eliminated (Monaco & Major, 2012). Over 300 drug failed to affect progression (Wolinsky et al., individuals on natalizumab for MS have developed 2007). A trial in secondary progressive MS of inter- PML since 2006, and 22% of them have died. Previous feron beta-1a subcutaneous injection was also negative exposure to JCV provokes the development of anti- with respect to effect on progression (Kappos, Polman, bodies to JCV. Individuals with antibodies to JCV are Pozzilli, Thompson, & Dahlke, 1998). more likely to develop PML. By 24 months of treat- The interferon preparations are slightly different in ment, in antibody-positive patients with JCV, the risk that interferon beta-1b is produced in modified E. coli of developing PML is approximately 1:200 (Monaco cells and interferon beta-1a is produced in mamma- & Major, 2012). If an individual is JCV antibody- lian cells. Both interferon beta-1b and interferon beta-1a positive and has had previous immunosuppressant work similarly by reducing peripheral antigen presen- treatment, the risk of PML increases to approximately tation and T-cell proliferation. Furthermore, interferon 1:100 (Monaco & Major, 2012). beta may downregulate adhesion molecules at the level Approved in 2010, fingolimod is the first FDA- of the blood brain barrier. All interferon preparations approved oral agent for the treatment of RRMS. have shown efficacy in relapse reduction and disability Fingolimod is a sphingosine 1-phosphate inhibitor outcomes. In addition, whether in phase 3 regulatory that works by depriving naive and central memory trials or subsequent trials, interferon preparations have T-cells of a signal to egress from secondary lymph shown efficacy for improving MRI outcome measures organs. Results from two large phase 3 trials indicated and have indicated favorable long-term safety (Herndon that a 0.5-mg daily dose of fingolimod significantly et al., 2005; Kappos et al., 2006b; Reder et al., 2010). reduced annualized relapse rate, MRI activity, and dis- Glatiramer acetate is a synthetic polypeptide ability progression (Cohen et al., 2010; Kappos et al., similar to myelin basic protein. It is thought to work 2010). Sphingosine 1-phosphate receptors are found

Copyright © 2013 American Association of Neuroscience Nurses. Unauthorized reproduction of this article is prohibited. S18 ora fNuocec Nursing Neuroscience of Journal Copyright © 2013 American Association of Neuroscience Nurses. Unauthorized reproduction ofthis article is prohibited. TABLE 2. FDA-Approved Disease-Modifying Treatments for MS (Gold, 2011; Hartung et al., 2002; Jacobs et al., 1996; Johnson et al., 1995; Kappos et al., 2008, 2010; Killestein et al., 2011; Polman et al., 2006; PRISMS [Prevention of Relapses and Disability by Interferon Beta-1a Subcutaneously in Multiple Sclerosis] Study Group, 1998; The IFNB Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group, 1995) Treatment Dose Indication Proposed MoA Side Effects Interferon beta-1b 250-mcg SC qod Relapsing forms of MS and CIS Anti-inflammatory, antiproliferative Flu-like symptoms, elevated hepatic activity on T-cells enzymes, injection site reactions, possibly depression Interferon beta-1a 30-mcg im weekly Relapsing forms of MS and CIS Anti-inflammatory, antiproliferative Flu-like symptoms, elevated hepatic activity on T-cells enzymes, injection site reactions, possibly depression Interferon beta-1a 22- or 44- mcg SC Relapsing forms of MS and CIS Anti-inflammatory, antiproliferative Flu-like symptoms, elevated hepatic thrice a week activity on T-cells enzymes, injection site reactions, possibly depression Glatiramer acetate 20-mg SC daily Relapsing forms of MS and CIS Immune system shift to less Injection site reactions, immediate inflammation postinjection reaction with flushing, tachycardia, dyspnea Natalizumab 300-mg iv every Relapsing forms of MS, generally Binds to VLA4 on cell surface to Headache, infections, infusion 28 days recommended for those who have had prevent adhesion reactions possible, may provoke inadequate response or intolerability progressive multifocal to other MS medications leukoencephalopathy Fingolimod 0.5 mg by mouth daily Relapsing forms of MS Sequesters activated lymphocytes in Headache, increased risk of secondary lymph organs infections, first dose bradycardia, macular edema, dyspnea, GI upset Dimethyl fumarate 120 mg twice daily Relapsing forms of MS Induces T-cell apoptosis, potentially Flushing, bloating, diarrhea, (starting dose) or protects against oxidative stress, inhibits lymphopenia, and eosinophilia 240 mg twice daily adhesion molecules, and potentially (maintenance dose) shifts the immune response toward a Th-2 (helper T-cell) response Teriflunomide 7 or 14 mg daily Relapsing forms of MS Inhibits dihydroorotate dehydrogenase, Gastrointestinal upset, hair thinning, thus reducing T- and B-cell activation, hepatic enzyme elevation, mild proliferation, and response to neutropenia, and mild blood pressure autoantigens elevations Mitoxantrone 12 mg/m2 to maximum Worsening relapsing MS, secondary Immunosuppressant Leukopenia, alopecia, nausea, of 140 mg/m2 progressive MS, progressive relapsing MS infections, amenorrhea, reduced LVEF

Note. FDA = Food and Drug Administration; MS = multiple sclerosis; MoA = mode of action; SC = subcutaneous; qod = every other day; CIS = clinically isolated syndrome; im = intramuscular; iv = intravenous; GI = gastrointestinal; LVEF = left ventricular ejection fraction. Supplement to: Volume 45 & Number 6S & December 2013 S19 on many different cells, and thus, unwanted side effects elevation, mild neutropenia, and mild blood pressure from fingolimod may occur. Fingolimod is associated elevations (O’Connor et al., 2011). Teriflunomide is with bradycardia, particularly on the first dose. Patients contraindicated in pregnant patients and patients with must be observed for 6 hours after the first dose for any severe hepatic impairment (Aubagio, 2013). heart rate or blood pressure issues (Ginsberg et al., DMF, an oral treatment administered twice daily, 1995). An electrocardiogram is to be obtained before was approved for relapsing MS in March 2013. DMF dosing and at the completion of the observation is thought to work in MS by several potential me- period. In May 2012, the FDA revised the labeling chanisms. It has been found to induce T-cell apopto- of fingolimod to include the following contraindica- sis, potentially protect against oxidative stress, inhibit tions (Ginsberg et al., 1995): adhesion molecules, and potentially shift the immune response toward a Th-2 (helper T-cell) response (Gold, Patientswhointhelast6monthsexperiencedmyo- 2011; Kappos et al., 2008; Killestein et al., 2011). cardial infarction, unstable angina, stroke, transient Results of a large, randomized, placebo-controlled, ischemic attack, decompensated heart failure requir- phase 3 trial of DMF in patients with RRMS showed ing hospitalization, or Class III/IV heart failure. that DMF (240 mg) was associated with significant History or presence of Mobitz Type II second-degree reductions in the annualized relapse rate, a signifi- or third-degree atrioventricular block or sick sinus cant reduction in the probability of disability pro- syndrome, unless patient has a functioning pacemaker. gression (based on the Expanded Disability Status Baseline QTc interval of Q500 milliseconds. Scale) and a reduction in MRI measures of disease Treatment with Class IA or Class III anti-arrhythmic progression (Abad, Gomez-Outes, Martinez-Gonzales, drugs. & Rocha, 2006). Side effects of DMF include flushing, bloating, diarrhea, lymphopenia, and eosinophilia Lymphopenia and hepatic enzyme elevations are (Kappos et al., 2008). possible side effects, and laboratory monitoring is necessary. Herpes infections, including varicella zoster, Emerging Therapies were seen in clinical trials, and it is recommended that There are numerous new treatments in late-stage de- all patients have a varicella-zoster titer before the ini- velopment in the MS research pipeline. Those agents tiation of treatment and vaccination before treatment that have completed or are in phase 3 trials include if no titer is detected. Macular edema has been ob- laquinimod, alemtuzumab, and daclizumab. Laquinimod served in patients receiving fingolimod (Cohen et al., is an oral treatment, alemtuzumab is administered intra- 2010; Kappos et al., 2010). Blood pressure eleva- venously once yearly over several days, and daclizumab tions have also been observed with fingolimod use is administered subcutaneously every 2 or 4 weeks. (Ginsberg et al., 1995). Alemtuzumab is currently under FDA review for po- Teriflunomide was approved for relapsing MS in tential approval as a DMT for MS. September 2012. Teriflunomide is an oral treatment administered once daily. The approved doses are 7 mg Laquinimod once daily and 14 mg once daily. It is a derivative of Laquinimod is a small molecule related to linomide, leflunomide, which is FDA approved for the treat- which was tested in MS. Linomide appeared prom- ment of rheumatoid arthritis. This agent works by ising as an MS treatment; however, serious cardiac inhibiting dihydroorotate dehydrogenase, which is events resulted in the termination of clinical trials. necessary for deoxyribonucleic acid replication. It re- Laquinimod, although structurally similar, has not been duces T-cell and B-cell activation, proliferation, and associated with cardiac events. The mechanism of ac- response to autoantigens. Two randomized, double- tion of laquinimod is not known, but it is believed blind, placebo-controlled clinical trials met the relapse to shift the immune response to a less inflammatory rate and disability end points (14-mg dose; Freedman response (Gasperini & Ruggieri, 2011). Additional et al., 2013; O’Connor et al., 2011). Both approved investigations have shown the inhibition of adhesion doses (7 and 14 mg) were shown to be superior com- molecules at the level of the blood brain barrier with pared with placebo for the MRI outcomes of total laquinimod (Wegner et al., 2010). Laquinimod may lesion volume and Gd enhancement (O’Connor et al., also affect the CNS. Laquinimod was evaluated in 2011). In a separate randomized, double-blind trial, two large phase 3 trials of RRMS (Comi et al., 2012b; teriflunomide (14 mg) was shown to be comparable Vollmer, 2011). The first phase 3 trial, known as the with interferon beta-1a for the annualized relapse rate ALLEGRO trial, showed a reduction in the annual- outcome (Vermersch et al., 2012). Adverse events re- ized relapse rate of 23% in the laquinimod group ported with teriflunomide have included gastrointes- relative to placebo (p G .0024). In addition, there was tinal upset, temporary hair thinning, hepatic enzyme a 36% decrease in the risk for disability progression,

as measured by the Expanded Disability Status Scale (p = .008; Jeffrey, 2011). Adverse events, including compared with placebo (p = .0122) and a 32.8% re- idiopathic thrombocytopenia purpura, autoimmune duction in brain volume loss (p G .0001; Comi et al., thyroid disease, infusion-related reactions, and in- 2012b). creased risk for infections, were observed in the clin- The second phase 3 trial of laquinimod, known as ical trials (Jeffrey, 2011). the BRAVO trial, included 1,106 patients with RRMS. That trial consisted of a laquinimod arm, a placebo Daclizumab arm, and a rater-blinded comparator arm of interferon Daclizumab is a monoclonal antibody against the beta-1a. The trial failed to meet the primary end point interleukin-2 receptor that binds to CD-25. It has of relapse rate reduction. It was determined that the been found to decrease abnormal T-cell activation baseline MRI characteristics of the treated and placebo and may also increase the population of regulatory groups were different, which may have accounted for natural killer cells. Daclizumab has been adminis- the missed end point. After adjusting for the differ- tered by intravenous infusion and, more recently, by ences, the results were statistically significant, with a subcutaneous injection. Two phase 2 trials have been 21% reduction in relapses (p = .26), a 33.5% decrease completed that indicate efficacy in relapse reduction in risk of disability progression (p = .044), and a and MRI outcomes (Giovannoni et al., 2011; Wynn 27.5% reduction in brain volume loss (p G .0001; et al., 2010). The SELECT trial was a 1-year, ran- Vollmer, 2011). domized, double-blind trial that compared 150 and Side effects of laquinimod were mild and included 300 mg of monthly subcutaneous daclizumab to mild liver function test elevations, mild arthralgia, ele- placebo. Both treatment groups reduced annual relapse vated erythrocyte sedimentation rate, and increased rate by approximately 50% (p = .0002). New and en- rates of infection in the treated groups. There were larging T2 MRI lesions were reduced by 70%Y78% no cardiac events reported with laquinimod treatment (p G .0001; Giovannoni et al., 2011). A second phase 2 (Comi et al., 2010; Gasperini & Ruggieri, 2011). At trial, the CHOICE trial, was a 24-week study of this time, laquinimod will not be submitted to the 230 patients with RRMS who had at least one relapse FDA for approval. However, plans are underway for or Gd-enhancing lesion in the brain or spinal cord regulatory approval in Europe. while on stable interferon beta therapy. Patients were randomized to receive high-dose daclizumab (2 mg/kg Alemtuzumab every 2 weeks subcutaneously plus interferon beta), Alemtuzumab is a humanized anti-CD52 monoclonal low-dose daclizumab (1 mg/kg every 4 weeks sub- antibody. It has been used and is FDA approved for cutaneously plus interferon beta), or interferon beta the treatment of chronic lymphoid leukemia. CD-52 plus placebo. The primary outcome was new or en- is expressed on a variety of cell types, including T hancing MRI lesions, and a significant 72% reduction and B lymphocytes, monocytes, and macrophages; was observed in the number of new or enlarging T2 alemtuzumab depletes these cells rapidly after infu- MRI lesions in the high-dose daclizumab plus inter- sion. Alemtuzumab is dosed once yearly by intrave- feron beta group compared with the interferon beta nous infusion daily for 5 days. In the second year of plus placebo group (p = .004). Adverse events in- clinical trials, the dosing was daily for 3 consecutive cluded rash and infections consisting mainly of urinary days. Alemtuzumab was evaluated in two large phase tract and respiratory tract infections (Wynn et al., 2010). 3 trials (Comi et al., 2010; Jeffrey, 2011). Of note, Mild lymphopenia and mild elevations in hepatic en- both trials compared alemtuzumab with interferon zymes have also been observed with daclizumab treat- beta-1a three times weekly, and there was no placebo ment (Martin, 2012). A phase 3 trial of daclizumab arm in either trial. The first trial included 581 DMT- is currently in progress. naive patients, and the results showed a 55% reduction in relapses in the alemtuzumab group relative to the interferon group (p G .0001). The disability end Summary point was not met in that trial (Comi et al., 2010). In MS is a complex disease that causes widespread demy- the second phase 3 trial, 840 patients who had break- elination and axonal damage of white and gray matter, through disease were eligible for participation, and leading to often irreversible damage and disabling neu- again, the comparator arm was interferon beta-1a by rological symptoms. Diagnosis of MS is often difficult subcutaneous injection three times a week. In this and requires clinical and paraclinical information, along trial, there was a 49% reduction in the annualized re- with the exclusion of other possible causes of symp- lapse rate in the alemtuzumab arm compared with in- toms. An international panel has developed and revised terferon beta-1a (p G .0001). The disability end point diagnostic criteria for MS to expedite the diagnosis was met with a 43% reduction in sustained disability and to improve diagnostic accuracy.

Since 1993, 10 medications have received FDA Aubagio. (2013). Aubagio (teriflunomide) tablets for oral admin- approval for MS: nine for RRMS and mitoxantrone istration. Initial US approval: 2012. Available at http:// for worsening relapsing and secondary progressive MS. products.sanofi.us/aubagio/aubagio.pdf Barkhof, F., Calabresi, P. A., Miller, D. H., & Reingold, S. C. Interferon beta-1a weekly injections and interferon beta-1b (2009). Imaging outcomes for neuroprotection and repair subcutaneous injections, as well as glatiramer acetate, in multiple sclerosis trials. Nature Reviews Neurology, 5, are approved for CIS and RRMS. These injectable 256Y266. treatments have shown long-term efficacy and long- Calabrese, M., Rinaldi, F., Mattisi, I., Bernardi, V., Favaretto, A., term safety. The more recent treatments natalizumab, Perini, P., & Gallo, P. (2011). The predictive value of gray matter atrophy in clinically isolated syndromes. 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