Multiple Sclerosis Therapeutics

Multiple Sclerosis Therapeutics......Page 2
Title......Page 4
Copyright......Page 5
Contents......Page 6
Contributors......Page 9
Abbreviations list......Page 14
Foreword......Page 16
Preface......Page 18
Progressive destructive pathology starts early in the disease......Page 20
Evolution of the MS disease process– the “MS categories”......Page 21
Heterogeneity in pathological mechanisms......Page 22
Clinical measures: relapses, physical function, neuropsychological performance (Chapters 6–8)......Page 23
Conventional MRI measures (Chapters 9,11)......Page 24
Relevance  of MRI lesions......Page 25
Declining disease severity in contemporary MS trials......Page 26
References......Page 27
Inflammatory demyelination as a cause of axonal loss......Page 31
Loss of axons by immune-mediated mechanisms......Page 32
Degeneration of chronically demyelinated axons......Page 33
Pathology of cortical lesions......Page 34
Neuronal damage in cortical lesions......Page 35
Functional consequences......Page 36
References......Page 37
How firm is the autoimmune hypothesis in MS?......Page 39
A framework to describe the immunology of MS......Page 40
Evidence for involvement of auto-reactive T-cells in MS......Page 41
Autoreactive T-cells may be activated by auto-antigens or by foreign antigens through molecular mimicry......Page 42
T-cell differentiation into functionally distinct subsets influences autoimmune disease outcome......Page 43
B-cells as important regulators of T-cell responses in MS (Chapter 42)......Page 44
Immune cell invasion into the CNS: more than one route......Page 45
Relative importance of CD4 vs. CD8 T-cells......Page 46
B-cell responses within the CNS......Page 47
References......Page 48
4 The genetics of multiple sclerosis......Page 54
The HLA locus and MS susceptibility......Page 56
Genotype--phenotype associations......Page 57
Biomarkers of disease progression......Page 60
Key terms......Page 61
References......Page 62
Changing face of multiple sclerosis......Page 65
Traditional prognostic factors......Page 66
Other factors which may influence prognosis......Page 68
Comorbid diseases......Page 70
Novel treatment targets and epidemiological studies......Page 71
References......Page 72
Introduction......Page 75
Methodological issues in measuring impairment and disability......Page 76
Surrogate outcomes......Page 77
Outcomes and the Multiple Sclerosis Functional Composite......Page 78
Potential improvements to the Multiple Sclerosis Functional Composite......Page 81
References......Page 82
7 Assessment of neuropsychological function in multiple sclerosis......Page 84
Clinical trials of disease-modifying medications......Page 85
Factors complicating NP outcome assessment in MS trials......Page 87
Recommendations for design and analysis of NP outcome assessment in MS trials......Page 90
References......Page 93
Role of health-related quality of life assessment in the conduct of evidence-based medicine......Page 98
Definition......Page 99
Standard gamble......Page 100
Item response theory and computer adaptive testing......Page 101
Health services research......Page 102
Randomized clinical trials in MS that included HRQoL measures......Page 103
References......Page 106
A brief primer in the basis of MR as applied to MS......Page 110
“Typical” lesion formation......Page 111
Heterogeneity of enhancing lesions......Page 112
“Atypical” lesion formation (see also Chapter 13)......Page 113
Evolution of cMRI-monitored disease......Page 114
Enhanced lesion behavior over time......Page 115
Enrichment......Page 116
Enhancing lesions and disability......Page 117
Contrast dose and scan timing......Page 118
T2 lesion behavior over time......Page 119
T2 lesion counts......Page 120
Are enhancing lesion and T2 lesion counts equivalent?......Page 121
The pathologic substrate......Page 122
T1-hypointense disease burden......Page 123
Clinical significance of T1-hypointense lesions......Page 124
References......Page 125
Physical basis of MT-MRI......Page 131
Analysis of MT-MR images......Page 132
MT-MRI to assess tissue damage within macroscopic white matter lesions of MS......Page 133
MT-MRI changes in active MS lesions......Page 134
MT-MRI lesion load......Page 135
MT-MRI to assess damage of MS tissues appearing normal on conventional MRI scans......Page 136
Normal-appearing white matter and normal-appearing brain tissue......Page 137
MT-MRI studies of the cervical cord and optic nerve in MS......Page 138
MT-MRI and clinical trials of MS......Page 139
Conclusions......Page 140
References......Page 141
Methods for estimation of atrophy......Page 147
Segmentation-based approaches......Page 148
Methods for measurement of gray matter and white matter atrophy......Page 150
Methods for measurement of atrophy in brain structures and lobes......Page 151
Confounding issues in atrophy measurements......Page 152
Natural history of atrophy in MS......Page 153
Correlations between atrophy and other MRI measurements......Page 155
Correlations between atrophy and disability......Page 157
Atrophy in MS clinical trials......Page 159
References......Page 162
Mechanisms of acute conduction block......Page 169
Mechanisms of chronic functional impairment: the "axonal hypothesis"......Page 170
The NA resonance......Page 171
Measurement issues......Page 173
1H-MRS(I) findings agree with histopathological evidence of axonal damage in  patients with MS......Page 174
1H-MRS(I) measurements of NA correlate with measures of clinical disability in patients with MS......Page 175
Implications for understanding the natural history and treatment of patients withMS......Page 176
References......Page 178
Features of gray matter pathology in MS......Page 184
Conventional MRI......Page 185
MR spectroscopy (Chapter 12)......Page 187
Magnetization transfer imaging (Chapter 10)......Page 188
Functional MRI (Chapter 14)......Page 189
Spinal cord imaging......Page 190
Future perspectives......Page 191
References......Page 192
Functional imaging methods......Page 194
Functional magnetic resonance imaging (fMRI)......Page 195
MS-specific challenges......Page 196
Fatigue......Page 197
Motor system......Page 198
Cognition......Page 199
Interpretation of cortical reorganization......Page 200
References......Page 201
Diffusion imaging: the basics......Page 205
DWI in MS......Page 206
DTI in MS: MD and FA lesion and whole-brain approaches......Page 207
Histopathology, electrophysiology, and DTI measurements:  and......Page 208
DTI enabled pathway-specific measurements in MS......Page 209
Diffusion imaging in routine clinical care and clinical trials......Page 211
References......Page 212
Rationale for MRI as an outcome measure in MS clinical trials......Page 217
New or enlarged T2-hyperintense lesion number......Page 218
Exploratory MRI measures for clinical trials......Page 219
Spinal cord atrophy......Page 220
Monitoring safety......Page 221
MRI in Phase 2 trials......Page 222
Statistical considerations with use of MRI in trials (see also Chapter 21)......Page 223
Practical aspects of image analysis in trials......Page 224
References......Page 227
Features and advantages of OCT imaging......Page 232
Multiple sclerosis and optic neuritis as specific models for visual pathway axonal loss......Page 235
Role for OCT in modeling axonal and neuronal loss in MS......Page 236
The future of retinal imaging in MS......Page 239
Neuromyelitis optica (NMO)......Page 240
References......Page 241
Institutional Review Boards and informed consent......Page 244
Maintaining the marketing authorization license......Page 245
Marketing authorization application......Page 246
Drug review and approval process in Asia......Page 247
Food and Drug Administration Amendments Act of 2007......Page 248
References......Page 249
Types of end-points......Page 251
Clinical end-points......Page 252
Physical disability outcome......Page 254
Other clinical evaluations and development of new end-points......Page 255
Biomarkers as outcome measures......Page 257
Understanding biomarkers and hazards of incorrect assumptions......Page 258
Conclusions......Page 260
References......Page 261
Long-term RCTs......Page 263
Long-term non-randomized observational trials (NROTs)......Page 264
Methods to adjust for bias and confounding in NROTs......Page 265
Conclusions......Page 268
References......Page 269
The placebo problem......Page 272
Use of “virtual placebos”......Page 273
Adaptive randomization schemes......Page 274
Use of surrogate end-points to shorten the duration and size of a clinical trial......Page 275
Statistical considerations for adaptive designs......Page 276
Conclusions......Page 277
References......Page 278
Social and scientific value......Page 280
Favorable risk–benefit ratio......Page 281
Informed consent......Page 282
Respect for potential and enrolled subjects......Page 283
Equipoise......Page 284
BookmarkTitle:......Page 285
National multiple sclerosis task force......Page 286
Alternative clinical trial designs (Chapter 21)......Page 288
References......Page 289
The need for predictive biomarkers as a driver for pharmacogenomics research......Page 291
The role of “-omics” research in drug development......Page 293
Genotype-related studies of drug therapy response......Page 294
Gene expression (RNA) studies of drug therapy response......Page 297
Proteomics and metabolomics studies in MS......Page 299
Conclusions......Page 301
References......Page 302
IFN immunogenicity......Page 306
Measurements of anti-IFNβ antibodies......Page 307
Measurement of the bioactivity of IFNβ......Page 308
Clinical implications of IFNβ neutralizing antibodies......Page 309
Effect of NAbs on relapses......Page 310
Antibodies against natalizumab (see Chapter 27 for a review of natalizumab clinical trials)......Page 312
References......Page 314
Biological effects of interferon......Page 319
Mechanisms of action, and biomarkers......Page 320
Efficacy of IFNβ in multiple sclerosis: clinical trials and beyond......Page 321
Clinically isolated syndromes (Table 25.1)......Page 322
Relapsing–remitting MS (see Table 25.2 for pivotal trials; Table 25.4 for dose comparison trials)......Page 324
Progressive MS (Tables 25.3 and 25.4)......Page 326
Active arm comparison studies (Table 25.5)......Page 327
Observational studies (Table 25.6)......Page 328
Remaining issues and future directions......Page 329
References......Page 330
History of glatiramer acetate (copolymer 1)......Page 334
Immunomodulatory effects......Page 335
Pilot trial of GA in RRMS......Page 337
Extension of the Phase 3 trial......Page 338
BEYOND......Page 339
European/Canadian MRI study......Page 340
Open-label study of GA in MS over 15 years......Page 341
Combination trials......Page 343
References......Page 344
Background on natalizumab......Page 349
Pharmacokinetics and pharmacodynamics......Page 350
Phase 2 studies......Page 351
Monotherapy study......Page 352
Combination therapy with IFNβ-1a......Page 354
Combination therapy with glatiramer acetate......Page 356
Progressive multifocal leukoencephalopathy......Page 357
Remaining issues......Page 359
References......Page 360
Immunosuppressive and immunomodulatory actions......Page 363
The Phase 2 French and British multicenter controlled trial of mitox in RRMS or SPMS......Page 364
The Phase 3 randomized, double-blind, placebo-controlled, multicenter trial of mitox in progressive MS......Page 365
Use of mitox in early MS with malignant disease course. Observational study in 30 patients with clinical and MRI outcomes after one year......Page 367
Tolerability of mitoxantrone......Page 368
Cardiotoxicity......Page 369
Gonadal dysfunction......Page 370
What is the role of mitox for patients with SPMS without recent relapses?......Page 371
References......Page 372
Mechanism of action......Page 377
Early studies......Page 378
Clinical efficacy......Page 379
Safety......Page 382
References......Page 386
Sources of sphingosine 1-phosphate......Page 389
Sphingosine 1-phosphate receptors......Page 390
Pharmacology of fingolimod......Page 391
Inhibition of lymphocyte recirculation......Page 392
Potential direct central nervous system effects of fingolimod......Page 394
Phase 2 study in MS......Page 395
Transforms......Page 396
Cardiac effects......Page 397
Infection......Page 398
Conclusions......Page 399
References......Page 400
History of fumaric acid......Page 406
Phase 1 clinical trial......Page 407
Phase 2 clinical trial......Page 408
Summary......Page 410
References......Page 411
The biology of alemtuzumab......Page 412
Open-label experience of alemtuzumab treatment of multiple sclerosis......Page 413
Infusion-associated symptoms of alemtuzumab......Page 414
Anti-alemtuzumab antibodies......Page 415
References......Page 416
Evidence on efficacy from clinical trials......Page 426
Safety......Page 429
References......Page 430
Mechanism of action......Page 432
Phase 2 clinical trials......Page 433
Safety and tolerability......Page 434
References......Page 435
Teriflunomide: mechanism of action......Page 437
Teriflunomide: pharmacokinetic profile......Page 438
Teriflunomide monotherapy......Page 439
Teriflunomide adjunctive therapy with conventional DMTs......Page 440
Teriflunomide: safety profile......Page 441
Teriflunomide: overview of the clinical program......Page 442
References......Page 443
Molecular biology and mechanism of action......Page 445
Corticosteroids in relapsing MS......Page 446
HDMP for MS relapses......Page 447
Impact of HDMP on acute disease course......Page 449
Impact of HDMP on chronic disease course in relapsing MS......Page 450
Effects of HDMP on disease activity measured by imaging......Page 451
High-dose MP for anti-interferon neutralizing antibodies......Page 453
Toxicity of high-dose MP......Page 454
Implications for practice......Page 455
References......Page 456
Cyclophosphamide trials......Page 463
Cyclophosphamide in clinical practice......Page 464
Mycophenolate mofetil......Page 465
Azathioprine......Page 466
References......Page 468
IVIG treatment of acute relapses......Page 471
Clinically isolated syndrome......Page 473
Relapsing–remitting MS......Page 474
Post-partum use of IVIG......Page 476
Trials of IVIG to reverse fixed deficits......Page 477
Current recommendations on the use of IVIG in MS2,33,34......Page 478
References......Page 479
Apheresis methods......Page 481
Acute attacks of MS and other CNS demyelinating disease......Page 482
Progressive MS......Page 484
Neuromyelitis optica......Page 485
General considerations......Page 486
Frequency of complications......Page 487
Conclusions......Page 488
References......Page 489
Statins in treatment of experimental CNS autoimmunity......Page 492
Migration of immune cells into the CNS......Page 494
Statins as candidates for combination therapy......Page 495
References......Page 496
Targeting stages of the T-cell response......Page 499
Glatiramer acetate......Page 501
T-cell receptor vaccination......Page 502
Interleukin-12......Page 503
References......Page 504
IVIg and PLEX......Page 510
Immune modulators and suppressors developed to target T-cells......Page 512
Phase 1 re-treatment trial of rituximab in relapsing MS......Page 513
Exploratory end-points......Page 514
Pharmacodynamics and immunogenicity of rituximab in MS trials......Page 515
Ofatumumab......Page 516
What have we learned from B-cell depletion trials in humans?......Page 517
Roles of antibodies in MS......Page 518
B-cells as immune regulators......Page 519
References......Page 520
The effect of pregnancy on MS......Page 525
Estrogen treatment in an MS animal model: mechanisms......Page 526
General considerations......Page 528
Cortisol......Page 530
Acknowledgments......Page 531
References......Page 532
Types of stem cells......Page 535
Animal results......Page 537
Conditioning regimen......Page 538
Results of first-generation myeloablative hematopoietic stem cell transplantation protocols for secondary progressive multiple sclerosis......Page 539
Second-generation non-myeloablative autologous stem cell transplant protocols for relapsing–remitting multiple sclerosis......Page 541
Rationale for allogeneic hematopoietic stem cell transplantation for multiple sclerosis......Page 542
Hematopoietic stem cell transplantation using a composite graft of hematopoietic stem cells and mesenchymal stem cells......Page 543
References......Page 544
Overview of mesenchymal stem cells......Page 547
Effects on B-cells......Page 548
Neural repair potential of MSCs......Page 549
Factors affecting the characteristics of isolated MSCs......Page 551
Therapeutic transplantation of MSCs in humans......Page 552
Autoimmunity......Page 553
References......Page 554
Limitations of anti-inflammatory therapies......Page 562
Role of optical coherence tomography......Page 563
Macrophage and microglial activation......Page 564
Loss of trophic support by myelin......Page 565
Clinical trials of neuroprotective drugs in MS......Page 566
Exercise......Page 567
Other novel neuroprotective strategies......Page 568
Applications of stem cells to demyelinating disease......Page 569
References......Page 570
Rationale for combination therapy......Page 574
Considerations for designing trials of combination therapies......Page 575
CombiRx......Page 576
Sentinel......Page 577
NORMIMS......Page 578
Mitoxantrone......Page 579
Statins......Page 580
References......Page 581
Pharmacology and pharmacokinetics......Page 584
Clinical development of dalfampridine in multiple sclerosis......Page 585
References......Page 587
CAM use among individuals with MS......Page 589
Mind–body therapies......Page 590
Essential fatty acids......Page 591
Anti-oxidants......Page 592
Acupuncture......Page 594
Cannabis......Page 595
Recommendations for future research......Page 596
References......Page 597
Cerebral venous anatomy......Page 601
Spinal venous anatomy......Page 602
Findings of Zamboni and colleagues......Page 603
Challenges to CCSVI......Page 605
Studies funded by North American MS societies......Page 606
References......Page 607
Goals of disease therapy and the rationale for early treatment......Page 610
Adverse effects......Page 612
Natalizumab (see Chapter 27)......Page 613
Adverse effects......Page 614
Adverse effects......Page 615
Choosing a disease-modifying therapy in relapsing–remitting multiple sclerosis......Page 616
Measures of disease activity......Page 617
Criteria indicating need to change therapy......Page 618
Treatment options for continued disease activity......Page 619
Fulminant multiple sclerosis......Page 620
Treatment of progressive multiple sclerosis......Page 621
Conclusions......Page 622
References......Page 623
Characteristics of primary progressive multiple sclerosis......Page 631
Outcome measures......Page 632
Therapeutic agents......Page 633
Interferon beta-1a......Page 634
Trials which include patients with PPMS......Page 635
References......Page 636
Epidemiology and genetics......Page 641
First biomarker for any form of inflammatory CNS demyelinating disease......Page 643
NMO-IgG and disease severity......Page 644
Immunopathology......Page 645
In vitro evidence: AQP4 down-regulation, complement activation, EAAT2 down-regulation and blood–brain barrier disruption......Page 646
In vivo evidence – animal models......Page 647
Brain......Page 648
Non-organ specific......Page 650
Paraneoplastic NMO......Page 651
Attack prevention......Page 652
References......Page 654
Clinical presentation and clinical course......Page 659
First-line disease-modifying therapies......Page 660
Interferon beta......Page 661
Treatment failure......Page 662
Natalizumab......Page 663
Cyclophosphamide......Page 664
Psychosocial aspects of care and symptomatic therapies......Page 665
Affective disorders and depression......Page 666
References......Page 667
History of MRI in the diagnosis of MS......Page 672
MRI and the evaluation of the clinically isolated syndrome (CIS)......Page 673
Follow-up MRI and monitoring of MS by MRI......Page 675
Future directions......Page 677
References......Page 678
Effects of concurrent medication......Page 681
Cognition and cognitive fatigability......Page 682
Pathogenesis......Page 683
Autonomic nervous system dysregulation......Page 684
Non-pharmacologic approaches......Page 685
Medications......Page 686
References......Page 687
Spasticity-related impairment......Page 693
General considerations......Page 694
Baclofen......Page 695
Dantrolene sodium......Page 696
Botulinum toxin......Page 697
Intrathecal baclofen......Page 698
Conclusions......Page 699
References......Page 700
Suprasacral spinal cord effects......Page 703
History......Page 704
Lower urinary tract imaging......Page 705
Urodynamic evaluation......Page 706
Conservative therapy for failure to store urine......Page 709
Surgical management of bladder dysfunction......Page 711
Sexual dysfunction......Page 713
Treatment options for male sexual dysfunction......Page 714
Evaluation of female sexual dysfunction......Page 716
References......Page 717
Cognition......Page 723
Diagnosing depression in MS patients......Page 724
Treating MS depression......Page 725
Barriers to seeking and accepting treatment for MS depression......Page 727
Shoring up support: who cares for the caregivers?......Page 728
References......Page 730
Complexities and putative mechanisms of pain in MS patients......Page 734
Psychological aspects of pain......Page 735
Treatment approaches for pain and associated symptoms......Page 736
References......Page 739
Varicella......Page 741
Influenza......Page 742
Interferon beta......Page 743
Estrogen......Page 744
Vitamin D......Page 745
Thyroid disease......Page 746
Narcolepsy......Page 747
References......Page 748
Difficulties in implementing rehabilitation in individuals with MS......Page 751
Disease-specific measures......Page 752
Conclusions......Page 755
References......Page 756
Index......Page 758