Monday, December 10, 2007

ECTRIMS 2007: Understanding MS: Pathogenesis, Neuroinflammation, and Degeneration CME

The materials presented here were prepared by independent authors under the editorial supervision of Medscape and do not represent a publication of the European Committee for Treatment and Research in Multiple Sclerosis. These materials and the related activity are not sanctioned by the European Committee for Treatment and Research in Multiple Sclerosis or the commercial supporter of the conference and do not constitute an official part of that conference.

Release Date: November 29, 2007;

The Impact and Burden of Multiple Sclerosis
Prevalence, Epidemiology, and Economic Burden

The national and regional prevalence of multiple sclerosis (MS) in France was reported at the 2007 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) meeting, showing the overall prevalence in France and its 22 regions using the same methodology for the first time.[1] The computerized database of the National Health Insurance system (Caisse Nationale d'Assurance Maladie [CNAM]) assessed 80% of the French population or 54,974,101 people. The national and regional prevalence was estimated on October 10, 2004. There were 49,626 cases of MS on the CNAM database on the prevalence date. The national prevalence was 90.3 per 100,000 (2.6 female-to-male ratio). The northern and eastern regions had a higher prevalence (101.1-122.2 per 100,000) compared with the western and southern regions (78.5-84.3), with the central region having an intermediate prevalence (84.3-101.1 per 100,000). The prevalence in Northeast France was 1.5 times that of Southwest France. These observations are consistent with the previously reported data of the heterogeneous distribution of MS in Europe between Northern and Southern European countries.

In Japan there is a geographic phenotype difference in MS. Two distinct subtypes of MS occur in Asians: optic-spinal multiple sclerosis (OCMS or neuromyelitis optica) and conventional multiple sclerosis (CMS). From 4 nationwide surveys in Japan taken in 1972, 1982, 1989, and 2004, 9900 patients with MS were seen with a prevalence of 7.7/100,000.[2] OCMS was more common in southern Japan, whereas CMS was more common in the north. Peak age of onset in patients declined from their early 30s in 1972 to their early 20s in 2004. The proportion of patients with OCMS decreased over the observation period from 1972 to 2004. The frequency of CMS remained predominant in the northern regions.

In another epidemiologic presentation from Japan,[3] an increasing incidence of MS in the Tokachi province of Hokkaido (the northernmost island of Japan) was noted over a 30-year period. Two epidemiologic surveys were conducted to assess the prevalence of MS in 2001 and 2006. The Tokachi province had a population of 350,000 in 2001 and 360,000 in 2006. In 2001 the prevalence of MS that satisfied the Poser criteria was 8.6/100,000 and 13.1/100,000 in 2006. The mean age at the prevalence day was 41.0 years old and the mean age at onset was 28.4. The mean duration of disease was 12.6 years. The rate of primary progressive MS was 4%; relapsing-remitting MS was 70%; and secondary progressive MS was 26%. The prevalence of OCMS was 1.7/100,000 in both 2001 and 2006 showing no change compared with CMS. From prior data, it was known that the mean annual incidence increase of MS was 0.15 from 1975 to 1989 but 0.68 from 1990 to 2004. It appears that the increased prevalence of MS in northern Japan may be due to the increased incidence since 1990.

Since disease-modifying therapies (DMTs) have been available, considerable healthcare resources are used by MS patients. A healthcare utilization survey was carried out from a Health Insurance Portability and Accountability Act (HIPAA)-compliant commercial administrative claims database. The database contained integrated inpatient, outpatient, and pharmacy records on over 12 million persons from all major US regions, with the diagnostic International Classification of Diseases, Ninth Revision (ICD-9) code for MS (340.xx) as the first or second diagnosis.[4] The time span analyzed ranged from June 2005 to June 2006. The results found 12,216 identified MS patients, 77% of whom were women, and 84% aged 30-59 years (mean, 47 years). Fifty-six percent used at least 1 DMT. Interferon (IFN) beta-1a (intramuscular) was most common (19.8%), followed by glatiramer acetate (19.4%), INF IFN beta-1a subcutaneous (10.2%), IFN beta-1b (9.2%), and mitoxantrone (0.9%). Six percent received 2 or more DMTs. Those who used DMT were more likely to use symptomatic treatments: Forty-three percent used medications for depression, 31% for spasticity, 25% for bladder symptoms, 19% for fatigue, and 28% for pain or dysesthesiae. Twelve percent of patients were admitted to a hospital (56% condition-related); 11% had emergency department visits (13% condition-related); 2.4% had intensive care unit stays (44% condition-related); and 1.8% had skilled nursing facility stays (58% condition-related). Even though DMTs are available to the majority of MS patients, only 56% of the MS patients in this particular survey chose to take DMTs, but a significant amount of healthcare resources was still used by this group creating costs beyond the cost of the DMTs. This could be interpreted to suggest that improved treatments are needed to reduce the current healthcare as well as personal burden of MS.

Impact on Patients' Quality of Life and Cognition

Studies examining the impact of stressful life events on MS exacerbations have given conflicting results. However, a study of war stress from the Carmel Medical Center in Haifa, Israel, after the Hezbollah-Israeli war in 2006, showed a significant increase in MS exacerbations compared with similar time periods prior to the war.[5] The influence of psychological coping strategies was also examined.

Participants in the study were 156 MS patients with relapsing-remitting MS, all residents of northern Israel who were followed regularly at the MS clinic. The number of severe relapses treated with steroids during and following the war were compared with similar time periods at the preceding year. Exposure to war events, resulting subjective stress, and psychological coping strategies were evaluated by means of structured interviews. The results of the study indicated that 18 relapses occurred compared with 1-7 relapses in similar time periods over the 13 months prior to the war (P = .001-.02, McNemar's test). The percentage of patients reporting intense stress among wartime relapse patients compared with remission patients was significant (44% vs 20%, P = .03). The percentage of patients reporting high levels of stress from rocket attacks was higher in relapsing patients (67% vs 42%, P = .05). Home evacuation stress was higher in relapsing patients (33% vs 11%, P = .02). Active coping mechanisms, such as planning ahead for home displacement, were used less frequently by patients with relapses (17% vs 47%, P = .01).

Three variables were selected as predictors of wartime relapse by a logistic regression model: subjective sense of stress, distress associated with displacement, and MS relapse in the previous year. Active coping reduced the risk for an exacerbation. The conclusions of the study indicated that the risk for an exacerbation is increased by wartime stress but can be reduced with active coping measures. This suggests a role for preventive measures in dealing with stress-related exacerbations.

Fatigue is the most frequent complaint of MS patients, even those with low Expanded Disability Status Scale (EDSS) scores. Fatigue affects quality of life for many individuals and is the main burden on the health and socioeconomic system. Two studies with longitudinal evaluation over 2 years analyzed variables in regard to fatigue in MS. In the study from the Karolinska Institutet in Stockholm, Sweden,[6] 219 outpatients were assessed every 6 months with the Fatigue Severity Scale (FSS). Personal and environmental factors (sex, age, sense of coherence, living with a partner, living with children, work status, and immunomodulatory treatment) were correlated. The results showed that the FSS varied over the 2 years, with 54% changing FSS category 1 or several times. Twenty-seven percent were persistently fatigued and 19% never fatigued. In those patients who had increased or persistent fatigue, mood and disease-related factors were significantly different: depression (P = .001), weak sense of coherence (P = .02), living with a partner vs not living with a partner (P = .02), not working (P = .05), more than 10 years since the diagnosis of MS and with a moderate EDSS score compared with a mild EDSS (P = .001), more than 10 years since the diagnosis of MS and with a moderate EDSS compared with a severe EDSS score (P = .02), and a moderately progressive course compared with a mild course (P = .001). The conclusions of this study were that fatigue persistently affected at least 27% of the MS population and that those with a moderate course were at greatest risk, especially with an associated depression.

Another longitudinal study of fatigue[7] showed that depression and physical impairment were significantly associated with persistent fatigue in a group of 267 MS patients followed over 2 years. Thirty-seven percent of the patients had persistent fatigue; 38% had sporadic fatigue; and 25% had no fatigue. Persistent and sporadic fatigue were not associated with disease duration, but they were significantly associated with physical impairment, primary progressive MS, insomnia, heat-sensitive fatigue, sudden-onset fatigue, and mood disturbance.

Cognitive Dysfunction

Studies have shown that up to 65% of MS patients have cognitive dysfunction and that cognitive dysfunction is the greatest cause for disability.[8] However, cognitive dysfunction is not well evaluated in the EDSS score nor in the routine office or clinic evaluation. There is a growing awareness that cognitive dysfunction in MS is underappreciated, and the large number of poster and platform presentations concerning cognition in MS at the ECTRIMS 2007 meeting reflects that awareness. It is important that both the practicing neurologist and academic neurologist take into consideration the cognitive function of their MS patients when evaluating the patient for DMT so that prevention of disability can be possibly achieved. Walking with a cane may not be a reason for loss of employment, but inability to follow or carry out directions or inability to formulate a plan of action may be disabling.

A significant percentage of patients with clinically isolated syndromes (CIS) were found to have significant cognitive dysfunction when evaluated with a comprehensive neuropsychological battery.[9] In an evaluation of 15 patients with CIS vs 15 healthy controls, 53.3% of the CIS patients compared with 0% of the controls had cognitive dysfunction. Patients were significantly impaired on tasks evaluating attention (46.6%), long-term verbal and nonverbal memory (33.3%), visuospatial skills (26.6%), executive function (20%), and learning (20%).

In a retrospective review of 71 MS patients with severe cognitive impairment in the first 10 years of their disease, 15 of the patients presented with cognitive impairment as their first and primary symptom.[10] The characteristics of these 15 patients were mean age of onset, 43 years old; 11 women, 4 men; and mean delay from symptom onset to diagnosis, 2.6 years. Oligoclonal bands in the cerebrospinal fluid were present in all but 1 patient. The cognitive dysfunction had a severe impact on daily living activities and remained the predominant feature of the disease for all patients even though physical disability remained mild (mild pyramidal, sensory, cerebellar, brainstem, or bladder signs in 11 of 15) or absent (in 4). Initial MRI pattern showed diffuse and confluent lesions in the periventricular white matter with severe cortical atrophy (n = 7, pattern A). Others showed focal white matter lesions typical of MS with little or no atrophy (n = 8, pattern B). Two patients' MRIs evolved from pattern B to pattern A in 2-5 years. Clinicians need to be aware that MS-related cognitive dysfunction can be disabling even with little or no physical disability.

Available Pharmacologic Therapies

There are 6 US Food and Drug Administration (FDA)-approved DMTs in the United States at this time. These DMTs are IFN beta-1a (intramuscular or subcutaneous), IFN beta-1b, glatiramer acetate, mitoxantrone, and natalizumab. All of these treatments have shown significant reduction of relapse rate and MRI lesions compared with controls. There are some data from pivotal studies to suggest a reduction of disability but long-term prevention of disability needs further evaluation.

Because cognitive dysfunction is the main cause of disability in patients with MS, and brain atrophy is highly associated with cognitive dysfunction, reduction of brain atrophy is a potentially important marker for the prevention of disability -- more important than the EDSS. In the AFFIRM study there was a more rapid brain parenchymal fraction (BPF) reduction in patients receiving natalizumab compared with patients receiving placebo during the first year (0.56 vs 0.24%) than the second year (0.24% vs 0.43%).[11] The question of why this may have occurred includes a time lag between inflammation and subsequent tissue loss (or atrophy in which the decrease in BPF during the first year may be an inevitable consequence of inflammation and tissue damage that occurred prior to initiation of treatment) or "pseudoatrophy" as an initial decrease in BPF from resolution of edema and inflammatory infiltrate rather than actual tissue loss.

To answer these questions, an analysis was conducted on the kinetics of brain atrophy during the first year of treatment with natalizumab from the AFFIRM study. Drs. Fisher and Rudick from the Cleveland Clinic Foundation, Cleveland, Ohio,[12] presented further evaluation of the kinetics of brain atrophy and the relationship between inflammatory lesions and BPF during natalizumab treatment. The study was a randomized, double-blind, placebo-controlled, phase 2 study of 213 patients, of which 148 (100 natalizumab, 48 placebo) had analyzable MRI scans. The scans were performed at 1 month prior to the study, at month 0 (baseline), monthly for 6 months, and at months 9 and 12. The 2 treatment arms of natalizumab (3 mg/kg and 6 mg/kg) were combined for all statistical analyses. The results showed an initial decrease in BPF in the early treatment period, followed by a leveling off after month 4 to the end of the treatment period (month 12). This pattern of BPF change is most suggestive of pseudoatrophy, which is consistent with an anti-inflammatory effect followed by a reduced atrophy rate in the late treatment phase. Therefore, this pattern of decrease in brain volume during the study suggests that natalizumab may have a beneficial effect on brain atrophy, beginning about 4 months after treatment initiation.

As of September 21, 2007, a total of 26,200 patients have been exposed to natalizumab,[13] with no new cases of progressive multifocal leukoencephalopathy reported. Seventeen thousand patients remain on natalizumab as of October 2007. The overall rate of serious hypersensitivity reactions is 0.64%, usually at the second infusion. Testing for the presence of persistent antibodies to natalizumab (detected on 2 occasions at least 6 weeks apart) prior to redosing following a prolonged dose interruption is recommended because reduced efficacy and increased risk for hypersensitivity reactions are more common in these patients. Twenty-four women in the United States and Austria with MS and exposure to natalizumab at any time during the first 3 months of pregnancy have enrolled in a pregnancy registry. Twenty-one pregnancies were ongoing as of August 23, 2007 with 1 live birth, 1 spontaneous abortion, and 1 elective abortion.

Nonpharmacologic Intervention

Physical therapy is a mainstay of patients of all types with physical disabilities. Studies of MS patients have shown variable results, probably due to many reasons, such as fatigue, instability of the disease, and small sample size. The type of physical therapy also varies. In a study from Belgium,[14] the benefit between bilateral exercise ("in-phase") and alternating exercise ("antiphase") was evaluated at various speeds of repetition for 10 weeks. Exercise rates of 0.75 Hz, 1.00 Hz, 1.25 Hz, and 1.50 Hz were used. Patients had mild-to-moderate disabilities (EDSS scores from 1.5 to 6.5). Coordination accuracy and stability were measured at baseline and at 10 weeks. The results showed that physical intervention programs with emphasis on strength do not influence motor control of the lower limbs after a 10-week intervention period. Antiphase training is performed with the lowest accuracy at the lowest frequency but improves when frequency increases. This is a particular finding in MS patients and contrasts with the current literature in regard to healthy subjects. This study also found that motor control and the EDSS were not correlated, probably due to the fact that EDSS is a rough picture of the distance that an MS patient can walk, whereas motor control is about stability and accuracy.

A comprehensive rehabilitation program showed improvement of MS patients with primarily pyramidal impairment and mild-to-moderate MS in both activities of daily living and mobility.[15] In a study with 200 patients in an inpatient multidisciplinary program, patients were assessed at the beginning and end of admission with the EDSS. Functional status was evaluated with the Barthel Index and Rivermead Mobility Index. Sixty-five percent were women, with a mean age of 50 and mean duration of disease of 17.3 years. All patients were enrolled in an individualized, goal-oriented, multidisciplinary inpatient program on the basis of practical skills of daily living. Results of rehabilitation were assessed in the whole sample as well as by comparing 3 subgroups: a mild group (EDSS 2-5.5), moderate group (EDSS 6-65), and severe group (EDSS 7-8.5). The results of the program showed greater improvement in patients in the mild and moderate groups, although the severe group did show some improvement. Pyramidal impairment was the greatest predictor of mobility and activities of daily living.

In another rehabilitation study,[16] patients were randomized to 3 treatment groups: outpatient, inpatient, and day hospital. There were 9 patients in each group for a total of 27 patients. The outpatient group (mean EDSS of 6.0) had 1-hour rehabilitation training twice weekly; the inpatient group (mean EDSS of 5.5) had more than 2 hours daily; and the day hospital group (mean EDSS of 6.5) had 2 hours daily. Outcome measures were Berg Scale, Barthel Index, and Hauser Ambulation Scale. The program lasted 5 weeks. The results showed that all patients improved in outcome measures except for ambulation, but there was no difference among the groups. The conclusion was that outpatient rehabilitation is equally effective as inpatient or day hospital therapy, and outpatient rehabilitation saves time and economic resources.

Supported by an independent educational grant from Genentech


Moreau R, Kazaz E, Clerc L, et al. Prevalence of multiple sclerosis in France and its 22 regions. Mult Scler. 2007;13(suppl2):S103. Abstract.
Osoegawa M, Fukazawa T, Fujihara K, et al. Temporal and geographical changes of multiple sclerosis phenotype in Japanese: nationwide survey results over 30 years. Mult Scler. 2007;13(suppl2):S101-102. Abstract.
Houzen H, Niino M, Kikuchi S, et al. Increasing risk of multiple sclerosis in Japan. Mult Scler. 2007;13(suppl2):S102. Abstract.
Chin P, Laouri M, Broder M, et al. Healthcare utilization among insured multiple sclerosis patients in the U.S. from 2005-2006. Mult Scler. 2007;13(suppl2):S261. Abstract.
Golan D, Somer E, Dishon S, et al. War stress, psychological coping mechanisms and exacerbations of multiple sclerosis. Mult Scler. 2007;13(suppl2):S238. Abstract.
Johansson S, Ytterberg C, Hillbert J, et al. A longitudinal study of variations in perceived level of energy and predictors of fatigue in multiple sclerosis. Mult Scler. 2007;13(suppl2):S115. Abstract.
Lerdal A, Celius EG, Krupp L, et al. Longitudinal patterns of fatigue in patients with multiple sclerosis. Mult Scler. 2007;13(suppl2):S114-115. Abstract.
Rao SM. Neuropsychology of multiple sclerosis. Curr Opin Neurol. 1995;8:216-220.
Kocer B, Nazliel B, Irkec C. Cognitive dysfunction in patients with clinically isolated syndrome. Mult Scler. 2007;13(suppl2):S114. Abstract.
Assouad R, Tourbah A, Sedel F, et al. Cognitive presentation in multiple sclerosis. Mult Scler. 2007;13(suppl2):S114. Abstract.
Miller DH, Soon D, Fernando KT, et al; AFFIRM Investigators. MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS. Neurology. 2007;68:1390-401.
Fisher E, Rudick R, Dalton CM, et al. The kinetics of brain atrophy during the first year of treatment with natalizumab. Mult Scler. 2007;13(suppl2):S168. Abstract.
Panzara M, Belcher G, Kooijmans M, et al. Use of natalizumab in patients with relapsing multiple sclerosis: updated safety results from TOUCH and TYGRIS. Mult Scler. 2007;13(suppl2):S169. Abstract.
Alders G, Gijbels D, Feys P, et al. The effect of physical intervention programs on coordination quality of the lower limbs in persons with multiple sclerosis. Mult Scler. 2007;13(suppl2):S132. Abstract.
Grasso MG, Triosi E, Tonin A, et al. Effectiveness of multiple sclerosis rehabilitation. Mult Scler. 2007;13(suppl2):S130. Abstract.
Giusti A, Viti B, Pirani G, et al. The effectiveness of neurological rehabilitation in multiple sclerosis: comparison between different rehabilitative settings. Mult Scler. 2007;13(suppl2):S130. Abstract.

Evaluating New Data for the Treatment of MS
New and Emerging Pharmacologic Treatments

Oral Therapies

Several new treatments for multiple sclerosis (MS) are in phase 2 or phase 3 trials. The combined analyses of subcutaneous cladribine were presented by Dr. S. Cook for the Cladribine Clinical Study Group.[1,2] The safety profile of cladribine at parenteral doses of up to 2.1 mg/kg was similar to placebo, with a sustained lymphocytic depleting effect consistent with its therapeutic mechanism. The parenteral trials included MS patients with relapsing remitting MS (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS). Since parenteral doses of 0.7 to 2.1 mg/kg can be achieved with oral preparations, 2 oral studies are now underway. One study, CLARITY, is a monotherapy, phase 3 trial for patients with RRMS and an Expanded Disability Status Scale (EDSS) score of 0-5.5 for a 2-year period. It has 3 treatment arms; Group 1 receives 10-mg cladribine tablets for 4-5 days on weeks 1, 5, 9, and 13 in the first year. Group 2 receives cladribine for the first 2 treatment periods but placebo for the third and forth treatments. Group 3 receives placebo for all 4 treatments.[3] At this time, enrollment is completed with 1329 patients. The primary efficacy parameter is the relapse rate from baseline to week 96. The other oral cladribine study, ONWARD, is a phase 2b study that combines IFN-beta-1a (subcutaneous 3 times weekly, 44 mcg) with oral cladribine in an otherwise similar design.[4] The primary efficacy parameter is number of new Gd+ T1 lesions from baseline to week 96. A new subcutaneous formulation of IFN-beta-1a is being used in this trial.

Two phase 3 trials are underway with an oral fumaric acid derivation (BG00012) in patients with RRMS.[5] BG00012 has been shown in vitro to inhibit expression of cytokines and adhesion molecules involved in inflammation, with resultant anti-inflammatory and neuroprotective effects. A phase 2b double-blind, placebo-controlled, 24-week study with a 24-week safety extension showed a significant 69% reduction of Gd+ T1 lesions at 720 mg/day of BG00012 compared with placebo. Additionally, patients receiving BG00012 had 48% fewer T2 lesions and 53% fewer T1 lesions compared with placebo (all P = .001). Two phase 3 studies are now underway: DEFINE (a double-blind, placebo-controlled study of 2 doses of BG00012 240 mg 2 or 3 times a day vs placebo) and CONFIRM (same design but with an added comparator of glatiramer acetate). They are 2-year studies of 1000 patients and 1200 patients, respectively, with RRMS and an EDSS score of 0-5.0. The primary efficacy parameter of DEFINE is the proportion of patients relapsing over the 2 years, and the primary efficacy parameter of CONFIRM is the rate of clinical relapse at 2 years.

Monoclonal Antibody Therapies

Alemtuzumab is a humanized monoclonal antibody against the T-cell antigen CD52 on lymphocytes. Two studies evaluating alemtuzumab (ALEM) in patients with RRMS were reported at the ECTRIMS meeting. One trial was in treatment-naive patients comparing 2 doses of ALEM (either 24 mg/day intravenously [IV] for 5 days at month 0 and for 3 days at month 12 or 12 mg/day) and subcutaneous IFN-I-beta 3 times weekly at 44 mcg.[6] At 2 years, 84.4% of low-dose ALEM patients were relapse free, 90.6% of high-dose ALEM patients were relapse free, and 60.4% of IFN patients were relapse free (P = .0002 low-dose and P = .0001 high-dose). ALEM improved disability on the Multiple Sclerosis Functional Composite (MSFC) and EDSS scores. Relapses were reduced and delayed. Safety findings associated with ALEM were immune thrombocytopenic purpura (ITT) and autoimmune disorders of the thyroid gland. The other trial with ALEM included MS patients who had failed prior treatment with any IFN. The patients had to have had the onset of MS in the last 5 years, EDSS scores of 0-6, IFN for at least 6 of the last 24 months, and 2 relapses.[7] Forty-five patients received 2 cycles of ALEM with 1 mg IV methylprednisolone prior to ALEM. Patients received ALEM 24 mg/day for 5 days (cycle 1) and then 24 mg/day for 3 days at month 12 (cycle 2). The result was a 9.3-fold reduction of relapse rate (relapses in 2 years prior to cycle 1 vs relapses in 2 years following; P = .0001). On disability measurements, 70% of patients had stable or improved MSFC. However, 4 cases of autoimmune thyroid disorder and 1 case of ITT developed in the 45 patients.

Daclizumab is a humanized monoclonal antibody that depletes CD25 from the cell surface of T cells and interacts specifically with the interleukin 2 receptor alpha chain (IL2RA). Daclizumab has shown promise as a therapy for both RRMS and SPMS in combination with INF and as monotherapy. The results of a recently completed phase 2 study with 230 patients with RRMS with EDSS scores of 0-5 and breakthrough disease while on any IFN were presented in a platform presentation.[8] There were 230 patients at 51 sites in North America and Europe. There was a 24-week double-blind, placebo-controlled treatment period and a 48-week washout period. There were 3 arms to the study: placebo add-on, 1 mg/kg subcutaneously every 4 weeks, or 2 mg/kg subcutaneously every 2 weeks. Primary endpoint was new Gd+ lesions between weeks 8 and 24. Secondary endpoints were relapse rate and safety issues. The results indicated a 25% reduction of Gd+ lesions with 1 mg/kg add-on of daclizumub (not significant [NS]) and a 72% reduction of Gd+ lesions with 2 mg/kg every 2 weeks (P = .004). Relapse rate reduction was 35% in each dosing group (NS). Daclizumab was safe and well tolerated, with no significant safety issues.

Individually Tailored Therapy for SPMS and PPMS

SPMS without exacerbations is often considered a nonmodifiable disease state. It is a phase of MS considered to consist of neurodegeneration with axonal loss and cortical and spinal cord atrophy. However, there are a few ongoing trials for SPMS. One involves the intravenous administration of a synthetic peptide, MBP8298, for SPMS patients with HLA haplotypes DR2 and/or DR4. MAESTRO-01 is a multicenter, multinational clinical trial in which over 600 patients have been enrolled.[9] An interim safety analysis of the first 508 patients, on a blinded basis, showed no significant safety concerns. An interim analysis of the first 200 patients at 2 years is expected in the third quarter of 2008. MAESTRO-03 is currently enrolling in the United States for SPMS patients without exacerbations to receive 500 mg MBP8298 or sterile water as placebo IV every 6 months.

Rituximab (RTX) is a monoclonal antibody that specifically targets CD20+ B cells. There may be a pathogenic role of B cells in MS, particularly in PPMS. In an ongoing placebo-controlled study, 439 patients with PPMS by the McDonald Criteria with greater than 1 year duration of disease, an EDSS score of 2-6.5, and cerebrospinal fluid (CSF) showing elevated IgG or oligoclonal bands in the past 24 months were randomized in a 2:1 manner to receive 1000 mg RTX twice every 24 weeks over 96 weeks (4 courses) or placebo.[10] The patients are to be followed to 122 weeks with magnetic resonance imaging at -2, 0, 6, 48, 96, and 122 weeks. Primary endpoint is a 1-point increase in the EDSS sustained for at least 12 weeks. Secondary outcomes are change in baseline to week 96, T2 lesion volume, and brain volume. Results of enrollment are that 50.3% of the 439 patients are female with a mean age of 50.4 years; 56% had a baseline EDSS greater than 4 with a mean EDSS of 4.03. Sixty-five percent of patients had never had a disease-modifying treatment. At randomization, there was a mean Gd+ lesion of 0.7 with 75.2% with no new lesions, but 24.8% had greater than 1 Gd+ lesion. These are pooled demographic data from an ongoing blinded study. With nearly 25% of patients with baseline Gd+ lesions and all patients with active CSF due to inclusion criteria, an enrichment for active disease in this trial is suggested. This is consistent with active immunologic activity in this patient population and may increase the possibility for a therapeutic effect of RTX.

Neuromyelitis Optica Treatment Options

Neuromyelitis optica (NMO; called spinal-optical MS in Asia and also called Devic's disease) is a serious, inflammatory, demyelinating disease of the optic nerves and spinal cord. Many patients fail to respond to steroid therapy or other standard treatments, including chemotherapy, for MS. Five-year survival may be less than 80%. Dr. Khatri[11] presented a series of 6 NMO patients who had failed high-dose methylprednisolone and prednisone treatment with plasma exchange (PE). All patients met diagnostic criteria for NMO and were serum NMO-IgG antibody positive. Three patients were white and 3 were African American (age range, 34-53; mean 40). All were female. EDSS ranged from 2 to 8.5 (mean 6.3). Following PE, all patients improved and stabilized (EDSS mean improved from 6.3 to 5.1). Four patients continue to receive PE (1 patient for the past 16 years). The frequency of maintenance PE varied from once a month to every 3 months. Because of insurance problems, 2 of the 4 patients had to stop PE for several months. This resulted in both patients becoming blind and bedridden, despite treatment with high-dose methylprednisolone and cyclophosphamide. When PE was restarted, there was dramatic improvement, although not to the prior functional state before it was stopped. The conclusion is that PE can be effective even on a long-term basis for some NMO patients refractory to other treatments.

Symptomatic Therapy

Fampridine-SR (a sustained-release form of 4-aminopyridine) can be useful in improving central conduction of demyelinated axons in the central nervous system (CNS) by closing potassium channels. Clinically, it has been shown in phase 2 and phase 3 trials to improve pyramidal tract function as measured by the timed 25-foot walk. A meta-analysis of a phase 2 and a phase 3 fampridine trial was presented in a platform presentation discussing the results of the trials, the efficacy assessments, and the clinical validity of outcome measures in the 2 trials. Both were double-blind, placebo-controlled, 14-week studies of MS patients with ambulatory deficits.[12] A total of 501 patients were included in the analysis, with a randomization ratio of 3:1 (drug:placebo). The results showed a significant improvement in ambulation for fampridine-treated patients over placebo (P = .001). The primary efficacy measurement was that of a "timed walk responder," which was a patient whose walking speeds for at least 3 of 4 treatment visits were faster than the fastest speed of any of the 4 pretreatment visits and one follow-up visit. Clinical impact was assessed with the 12-item Multiple Sclerosis Walking Scale, with significant improvement of fampridine over placebo patients (P = .001). Patient satisfaction was also high on both studies, with the Subject Global Impression score significantly better for fampridine treatment vs placebo (P = .001)

Low-dose naltrexone (LDN) has been popular among some MS patients as an alternative therapy. Naltrexone has long been approved by the US Food and Drug Administration as an orally administered treatment for heroin addiction. It is a semisynthetic opiate antagonist approved for use in a 50-mg dose. It has been used for the symptomatic treatment of pain, spasticity, and fatigue. In a study supported by the Italian Federation of Multiple Sclerosis, data supporting some benefit of LDN in PPMS patients were presented.[13] Prior evidence has shown that when naltrexone is given at very low doses (5 mg), an upregulation of endorphins results and no opiate antagonism occurs. In 40 PPMS patients treated with LDN in an open-label manner as a pilot study for safety, LDN has been safe so far. Transient liver function test elevation, mild agitation, and sleep disturbance have occurred as the main side effects. Only 2 dropouts have occurred, 1 for protocol violation and 1 for severely increased hypertonia. Efficacy results are pending, but patients reporting a sense of well-being may have a neurochemical basis for that effect.

Ethics of Placebo-Controlled Clinical Trials

Dr. Chris Polman discussed the ethics of placebo-controlled trials in the treatment of MS in a platform presentation on behalf of the National MS Society International Advisory Committee on Clinical Trials in MS, which met in Washington, DC in March 2007.[14] This committee updated the prior recommendation of the International Advisory Committee that had been published in 2001.[15] The recommendations of the current Committee are in context of the newly available treatment since 2001. The prior recommendations basically said that placebo-controlled trials were allowable "if certain conditions were met." These conditions have been expanded and are more restrictive. The current Committee recommendations for placebo-controlled trials to be ethical are: (1) if there is no existing effective therapy (EET) for their type of MS (such as for PPMS or most SPMS); (2) if the patient refuses treatment (such as with injectable medications); (3) if no EET has been effective for their type of MS (more than 1 adequate trial for each class of medication) or intolerable side-effects have occurred; (4) the patient must be well informed not only through the informed consent (IC) process but there also should be a patient advocate present; (5) there should be a separation between the treating neurologist and research neurologist; (6) the IC process should be repeated throughout the clinical trial to be sure that the patient is aware of all other treatment options; and (7) in areas that are "resource-restricted," the trial drug must be available to the subjects after the trial has been completed.

Supported by an independent educational grant from Genentech


Cook S. Combined analysis of the safety and tolerability of cladribine from four randomized, double-blind, parallel-group, placebo-controlled trials in patients with multiple sclerosis. Multiple Sclerosis. 2007;13(suppl 2):S244-245 (abstract).
Cook S. Safety profile of cladribine following repeat treatment: a combined analysis of data from five clinical trials in patients with multiple sclerosis. Multiple Sclerosis. 2007;13(suppl 2):S245 (abstract).
Giovannoni G, Comi G, Cook S, et al. The CLARITY study (CLAdRIbine tablets Treating multiple sclerosis orallY): design of a phase III trial of oral cladribine in relapsing multiple sclerosis. Multiple Sclerosis. 2007;13(suppl 2):S245 (abstract).
Montalban X, Cohen BA, Jeffery DR, et al. Oral cladribine added to interferon beta-1a for active multiple sclerosis: a 96-week, double-blind, placebo-controlled phase IIb study. Multiple Sclerosis. 2007;13(suppl 2):S245-246 (abstract).
Gold R, Fox R, Dawson K, et al. Two phase 3 studies to determine the efficacy and safety of BG00012, a novel, oral fumaric acid derivative, in patients with relapsing multiple sclerosis. Multiple Sclerosis. 2007;13(suppl 2):S173 (abstract).
Coles AJ; on behalf of the CAMMS223 Study Group. Alemtuzumab improved multiple sclerosis functional composite scores and delayed time to first relapse at 2-year interim analysis compared to subcutaneous interferon beta-1a. Multiple Sclerosis. 2007;13(suppl 2):S166 (abstract).
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Arfors L; on behalf of the MAESTRO-01 Investigators Group. Safety observations from administration of MBP8298 as part of the ongoing phase 3 MAESTRO-01 SPMS clinical trial. Multiple Sclerosis. 2007;13(suppl 2):S171-172 (abstract).
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Polman CH; on behalf of the National MS Society International Advisory Committee on Clinical Trials. A reconsideration of the ethics of placebo-controlled clinical trials in MS: outcomes of an international conference. Multiple Sclerosis. 2007;13(suppl 2):S17 (abstract).
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Exploring the Pathogenesis of MS and the Rationale for Current Treatments
Discussion of Key Cellular Players and Important Immune Responses

Dr. David Hafler presented a platform discussion reviewing the current and emerging understanding of the genetic basis of multiple sclerosis (MS).[1] Persons with a first-degree relative are known to be at higher risk than the average person. The prevalence of MS is 0.1% in the general population, 2% to 4% in siblings, 5% in dizygotic twins, and 30% in monozygotic twins. MS may be considered a complex genetic disease involving many genomic expressions. It has been known for over 30 years that there is a major histocompatibility complex (MHC) on chromosome 6p21. It is also known that MS is a disease that involves the dysfunction of the CD4+CD25 high regulatory T-cell function.

In order to further elucidate the genetic basis of MS, a collaborative effort of US and UK researchers used a staged approach to identify risk alleles associated with MS. The first stage involved whole genomic association scans using the Affymetrix 500,000 SNP (single nucleotide polymorphisms) GeneChip (Santa Clara, California) to analyze DNA from 931 trio families (an MS patient and both parents). The second stage involved further analysis of the most frequently appearing SNPs. Further analysis identified the 2 most prevalent SNPs, IL2RA and IL7R. Although IL2RA has been identified in both patients with MS and patients with diabetes, it is likely that different variants are associated with each of these diseases because the risk for MS and DM do not coexist. Although there may be different variants of the same gene for IL2RA, this may open up a new area for genetic typing in MS, which could lead to specific therapeutic choices for patients who may be more likely to respond to one type of treatment vs another. Genetic screening is currently being used in the MAESTRO-03 study. Data from the MAESTRO-1 study showed that patients with DR2 or DR4 haplotypes were likely to respond to treatment in secondary progressive MS (SPMS), while MS patients with other markers did not, so one of the inclusion criteria in the MAESTRO-3 study is a blood test on the screening visit. The patient must be DR2 or DR4 positive to be in the study.

In a platform presentation following Dr. Hafler's presentation, Dr. Howard Weiner discussed circulating markers that have been found to differ between relapsing remitting MS (RRMS) and SPMS.[2] The central question regarding MS treatment is whether early and aggressive immunotherapy will prevent the conversion to SPMS in the majority of patients. The specific identification of antibody patterns in MS may help achieve that goal because it is known that inflammatory antibodies are linked to brain pathology. The progression of RRMS to SPMS is likely to be due to neuronal degeneration triggered by inflammation.

Dendritic cells (DCs) are antigenic cells of the innate immune system that have the unique ability to induce primary immune responses. Circulating myeloid DCs were isolated from blood samples to determine if there were abnormalities in patients with MS and if myeloid DCs were related to disease stage. SPMS patients were found to have a greater percentage of myeloid DCs expressing CD80, IL-12, and TNF-alpha while having a lower percentage of PD-L1 compared with patients with RRMS or controls. A higher percentage of RRMS patients had DCs producing greater amounts of Th1 (IFN-alfa and TNF-alpha) and Th2 (IL-4, IL-13) compared with controls and SPMS patients. These results may be interpreted as showing that there is a loss of an inflammatory component in the immune system when MS patients transition from RRMS to SPMS. This may explain, in part, an immunologic basis for the different stages and clinical patterns of MS.

In a comparison of the treatment effects of FTY720 (a new oral treatment in human trials for MS), IFN-beta, and glatiramer acetate (GA) on experimental autoimmune encephalomyelitis (EAE), each of the 3 compounds were given to Lewis rats in a model of progressive EAE.[3] For decades, EAE has been the experimental model for MS. FTY720 was administered at 3 mg/kg orally. At this dose, the onset of acute EAE was inhibited, and when given after recovery from an acute attack in an untreated animal, FTY720 inhibited further relapses. When FTY720 was given at a dose of 6 mg/kg orally during an acute exacerbation, the progressive phase of EAE was inhibited. GA failed to prevent the progressive phase at doses of 10 mg/kg orally or 5 mg/kg subcutaneously. GA at doses of 15 mg/kg orally or 10 gm/kg subcutaneously failed to prevent the onset or severity of relapses of EAE. IFN-beta given at 10,000 U intraperitoneally 3 times weekly failed to prevent the progressive phase of EAE.

Cerebrospinal Fluid Analysis in Clinically Isolated Syndromes

Clinically isolated syndromes (CIS) have been extensively evaluated by clinical and magnetic resonance imaging (MRI) criteria for risk to develop clinically definite MS (CDMS). The clinical diagnostic value of cerebrospinal fluid (CSF) analysis was presented from 104 patients presenting with a first clinical episode consistent with a demyelinating disease of the central nervous system.[4] A diagnosis of either CIS or possible MS was made. The patients underwent neurologic evaluation, brain MRI, and CSF analysis and were followed from 2 to 6 years as to their course and final diagnosis according to the McDonald criteria. The results of the CSF evaluation showed a significant difference between the possible MS patients and CIS patients, with 82% of the possible MS patients having positive CSF for oligoclonal bands (IgGOB) while 18% of CIS patients had positive CSF for IgGOB. The conclusions of the authors were that "positive CSF" should be considered among the criteria of dissemination in time of lesions in MS.

Rating Scales

Optical coherence tomography (OCT) is a noninvasive and relatively inexpensive way to measure the retinal fiber layer. Dr. Siger and colleagues[5] presented data showing that by measuring the retinal nerve fiber layer (RNFL), the most proximal part of the optic nerve, a measure of axonal degeneration can be obtained. Fifty-one patients underwent OCT with RNFL measurements, 20 with optic neuritis (ON) and MS, 31 with MS and without ON, and 12 healthy controls. T2- and T1-weighted imaging lesion volume, T1/T2 ratio, and brain atrophy were analyzed and correlated with OCT. RNFL was also correlated with disease duration and neurologic status. The results showed that RNFL was significantly reduced compared with controls in the affected eye (ON) but not significantly different when compared with the unaffected eye. Reduction of RFNL was correlated with MRI measures of brain atrophy (P = .01) and increased T1 lesion (black holes) volume (P = .03). RNFL reduction also correlated with clinical data (Expanded Disability Status Scale: P = .004).

Supported by an independent educational grant from Genentech


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Authors and Disclosures

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Keith R. Edwards, MD

Assistant Clinical Professor of Neurology, Harvard Medical School, Boston, Massachusetts; Consulting Neurologist, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts

Disclosure: Keith R. Edwards, MD, has disclosed that he has served as an advisor or consultant to Allergan Pharmaceuticals, GlaxoSmithKline, Novartis Pharmaceuticals, Pfizer Pharmaceuticals, and Serono.

Iwona Misiuta, PhD, MHA

Scientific Director, Medscape LLC, New York, NY

Disclosure: Iwona Misiuta, PhD, MHA, has disclosed no relevant financial relationships.
Stephanie Kushner, PhD

Scientific Director, Medscape LLC, New York, NY

Disclosure: Stephanie Kushner, PhD, has disclosed no relevant financial relationships.