Multiple Sclerosis Therapy: Are We Ready for a One-Size-Fits-All Approach?

Bench to Bedside 63. Collins SM, Surette M, Bercik P. The interplay between the intestinal microbiota and the brain. Nat Rev Microbiol. 2012;10:735-742. 64. Pröbstel AK, Baranzini SE. The role of the gut microbiome in multiple sclerosis risk and progression: towards characterization of the "MS microbiome". Neurotherapeutics. 2018;15:126-134. 65. Wesemann DR, Portuguese AJ, Meyers RM, Gallagher MP, Cluff-Jones K, Magee JM, Panchakshari RA, Rodig SJ, Kepler TB, Alt FW. Microbial colonization influences early B-lineage development in the gut lamina propria. Nature. 2013;501:112-115. 66. Rosser EC, Oleinika K, Tonon S, Doyle R, Bosma A, Carter NA, Harris KA, Jones SA, Klein N, Mauri C. Regulatory B cells are induced by gut microbiota-driven interleukin-1b and interleukin6 production. Nat Med. 2014;20:1334-1339. 67. Ochoa-Repáraz J, Mielcarz DW, Haque-Begum S, Kasper LH. 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Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, Minnema MC, Lassen U, Krejcik J, Palumbo A, van de Donk NW, Ahmadi T, Khan I, Uhlar CM, Wang J, Sasser AK, Losic N, Lisby S, Basse L, Brun N, Richardson PG. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015;373:1207-1219. Puri KD, Di Paolo JA, Gold MR. B-cell receptor signaling inhibitors for treatment of autoimmune inflammatory diseases and B-cell malignancies. Int Rev Immunol. 2013;32:397-427. Byrd JC, Brown JR, O'Brien S, Barrientos JC, Kay NE, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Devereux S, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Pocock C, Thornton P, Caligaris-Cappio F, Robak T, Delgado J, Schuster SJ, Montillo M, Schuh A, de Vos S, Gill D, Bloor A, Dearden C, Moreno C, Jones JJ, Chu AD, Fardis M, McGreivy J, Clow F, James DF, Hillmen P; RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371:213-223. Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn I, Ghia P, Eradat H, Ervin T, Lamanna N, Coiffier B, Pettitt AR, Ma S, Stilgenbauer S, Cramer P, Aiello M, Johnson DM, Miller LL, Li D, Jahn TM, Dansey RD, Hallek M, O'Brien SM. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370:997-1007. Multiple Sclerosis Therapy: Are We Ready for a One-SizeFits-All Approach? Bruce A. C. Cree, MD, PhD, MAS M ultiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by demyelination, chronic inflammation, gliosis (plaques), and neuronal loss. MS plaques develop at different CNS locations over time (i.e., disseminated in space and time). Approximately 900,000 individuals in the United States and millions worldwide are affected (1). The clinical course is Department of Neurology, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, California The author has received personal compensation in 2016 and 2017 for consulting from Abbvie, Biogen, EMD Serono, GeNeuro, Novartis and Sanofi Genzyme. Address correspondence to Bruce A. C. Cree, MD, PhD, MAS, Department of Neurology, UCSF Weill Institute for Neurosciences, University of California San Francisco, 675 Nelson Rising Lane, Box 3206, San Francisco, CA 94158; E-mail: [e-mail] 258 extremely variable, ranging from a relatively benign condition to a rapidly evolving and incapacitating disease. MS is 3-fold more common in women than men. The mean age of onset is typically 30 years, but the disease can present across the lifespan. Approximately 10% of cases begin before 18 years of age, and an even smaller percentage begin before 10 years of age (2). Three clinical courses are recognized in MS (3). Relapsing MS (RMS) accounts for 85% of MS cases and is characterized by discrete attacks of neurological dysfunction that generally evolves over days to weeks. With initial attacks, there is often substantial or complete recovery over the ensuing weeks to months. However, as attacks continue, recovery may be less evident. Between attacks, patients are neurologically stable. For many patients who experience Cree: J Neuro-Ophthalmol 2018; 38: 251-262 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Bench to Bedside relapsing onset MS, at some point, the clinical course evolves such that the patient experiences deterioration in function unassociated with acute attacks, so called secondary progressive MS (SPMS). SPMS produces a greater amount of fixed neurologic disability than RMS. For a patient with RMS, the risk of developing SPMS is w2% each year, meaning that the great majority of RMS ultimately evolves into SPMS. Thus, SPMS seems to represent a late stage of the same underlying illness as RMS. The third clinical course is primary progressive MS (PPMS) that accounts for 15% of cases (4). These patients do not experience attacks but rather steadily decline in function from disease onset. Compared with RMS, the sex distribution is more even, the disease begins later in life (mean age w40 years), and disability develops faster (relative to the onset of the first clinical symptom). Despite these differences, PPMS seems to represent the same underlying illness as RMS. All 3 clinical courses are important for the neuroophthalmologist to recognize because MS can affect the visual system at any time, causing optic neuritis, diplopia, visual field deficits, and other symptoms affecting the vision pathway. No other animal but the human develops MS. Experimental autoimmune encephalomyelitis is an animal model in which purified myelin antigens are injected intraperitoneally with a proinflammatory adjuvant in certain strains of mice (5). This highly artificial experimental system, in which T cells play a central role mediating CNS inflammation, was proposed to explain MS. A very active laboratorybased community of scientists conflated EAE with MS and through their numerous publications triggered the widespread misconception that MS was a T cell-mediated autoimmune disease. In fact, there is less data from human biology that strongly support the supposition that autoreactive T cells are the primary mediators of MS. Nonetheless, EAE was widely used as a testing ground for development of many immune-based therapies, some of which were ultimately shown to impact disease activity in MS. One of the remarkable success stories of modern medicine is the development of disease modifying therapies (DMT) for long-term treatments of MS (6). Disease modifying therapies are proven to reduce the frequency of MS relapses. Some therapies are also recognized as being able to slow the accumulation of disability in MS. Early clinical trials in MS used immune suppression therapies such as cyclophosphamide, adrenocorticotropic hormone (ACTH) and plasmapheresis (7), azathioprine (8), methotrexate (9), and cladribine (10). These studies often grouped together relapsing and nonrelapsing subjects and were often relatively small in size or short in duration and consequently yielded unclear results. Pharmacological development in MS is an iterative process and with improvements in methodology to define the population under study, and select clearly interpretable endpoints, successful DMTs for MS were developed. The first DMT, interferon b-1b, was introduced in 1993 in Cree: J Neuro-Ophthalmol 2018; 38: 251-262 a limited access program and became widely available commercially in 1994. The field of treatment for relapsing onset MS has moved rapidly, and now, there are 13 (or 15 depending on how you count) U.S. Food and Drug Administration (FDA) therapies: IFN-b-1b (Betaseron or Extavia) (11), intramuscular IFN-b-1a (Avonex) (12), subcutaneous IFN-b-1a (Rebif) (13), Pegylated IFN-b-1a (Plegridy) (14), glatiramer acetate (Copaxone or Glatopa) (15,16), natalizumab (Tysabri) (17), fingolimod (Gilenya) (18), dimethyl fumarate (Tecfidera) (19), teriflunomide (Aubagio) (20), mitoxantrone (Novantrone) (21), alemtuzumab (Lemtrada) (22), daclizumab (Zynbrita) (23), and ocrelizumab (Ocrevus) (24,25). Although biologically diverse, all therapies have proposed mechanisms of action that affect immune function. The interferons are signaling molecules that influence gene transcription in primarily T lymphocytes although a variety of other cell types are also affected. Glatiramer acetate not only is believed to alter the polarization of T lymphocytes away from a proinflammatory phenotype (Th1) to a more regulatory phenotype (Th2) but also seems to effect how monocytes present antigen. Natalizumab is a monoclonal antibody that binds VLA4, a molecule expressed on both T and B lymphocytes, and prevents binding of VLA4 to VCAM1, a molecule expressed on the endothelial surface of vascular cells. Natalizumab prevents lymphocyte binding to the vascular endothelia, an important first step in the process of lymphocyte migration across the blood brain barrier. Fingolimod causes lymphocyte sequestration within the lymph nodes and spleen. The sequestered lymphocytes are no longer in circulation and therefore cannot cross the blood brain barrier to cause tissue injury. The mechanism of action of dimethyl fumarate is less well established; however, gene transcription networks within lymphocytes are altered after dimethyl fumarate treatment and upregulation of antioxidative enzymes might occur with treatment. Teriflunomide is an antiproliferative agent that inhibits replication of rapidly dividing lymphocytes that are presumed to constitute the autoreactive lymphocyte pool. Mitoxantrone is a cytotoxic chemotherapeutic agent that intercalates into DNA and cause topoisomerase-mediated DNA fragmentation during cell replication, resulting in lymphopenia. Alemtuzumab is an anti-CD52 monoclonal antibody that depletes 95% of both T and B lymphocytes. Daclizumab is a monoclonal antibody that binds to the interleukin-2 receptor and causes increased local concentrations of IL2. This cytokine stimulates proliferation of NK56bright cells, a suppressor cell that is believed to exert anti-inflammatory effects on other pro-inflammatory lymphocytes. Ocrelizumab is a CD20 monoclonal antibody that depletes primarily B cells, although a small subset of T lymphocytes that express CD20 at low levels are also depleted. Most treatments are available for newly diagnosed patients and some are recognized as treatments for patients 259 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Bench to Bedside after the first clinical MS attack. However, because of undesirable side effects some of these therapies are recommended for use after other therapies have been tried. Mitoxantrone is associated with cardiomyopathy and promyelocytic leukemia. Alemtuzumab is associated with de novo autoimmunity including thyroid disease, immune thrombocytopenic purpura and Goodpasture's glomerular basement membrane nephropathy, among others. Alemtuzumab is also associated with herpes virus reactivation and with listeria monocytogenes meningitis, conditions that require prophylactic antimicrobial treatment. Daclizumab is associated with fulminant hepatic failure. Natalizumab is associated with an increased risk of a rare, opportunistic infection: progressive multifocal leukoencephalopathy (PML). This often fatal or severely disabling brain virus infection was found to occur primarily in patients who tested seropositive for JCV antibodies, that is, antibodies directed against the virus that causes PML. This observation led to the realization that this medication could be more safely used in a subset of patients who tested negative for JCV antibodies (roughly 1/2 of MS patients). Fingolimod and dimethyl fumarate are also associated with a risk of PML although the risk is more than 2 orders of magnitude lower than for JCV seropositive natalizumab-treated patients. Because the CD20 monoclonal antibodies rituximab and ofatumumab were associated with PML, it is presumed that ocrelizumab will also carry a very low risk of PML, although PML has not yet been directly associated with ocrelizumab treatment. For the practicing clinician, the advent of iatrogenic PML, among other serious or potentially fatal complications, forcibly introduced a concept of varying risk: benefit profiles into the discussion about treatment options with our patients. With so many treatments from which to select, diverse mechanisms of action and the potential for serious medication-related complications, how should a busy clinician select the best therapy for any given patient? The clinical trials provide some insight about relative effectiveness, especially when head-to-head studies show clear evidence of superiority. Some patients present with highly active MS and in this setting many physicians feel confident about selecting therapies that are considered to have relatively greater efficacy. However, there is limited regulatory guidance as to which therapies should be used as "first-line" treatments for any given patient or which therapies should be "second-line" therapies, or what criteria should be used to decide that escalation to a potentially riskier but perhaps more effective therapy is warranted based on measures of disease activity despite treatment. Ocrelizumab is the first FDA-approved therapy for both relapsing and primary progressive MS. Ocrelizumab is administered as maintenance therapy by IV infusion (approximately 5-6 hours in duration) once every 6 months, a treatment regimen that is generally very well tolerated and associated with very high degrees of adher260 ence. In 2 head-to-head clinical trials, ocrelizumab was proved to be more effective on all outcome and radiographic measures compared with subcutaneous interferon beta-1a. The adverse event profile in these trials was also highly favorable with mild-to-moderate infusion reactions being the most common adverse events associated. Importantly, opportunistic infections did not occur after treatment. In a third placebo-controlled trial, ocrelizumab was superior at reducing clinical disability progression in primary progressive MS patients. As with the relapsing MS studies, ocrelizumab was generally well tolerated; however, a greater number of malignancies were reported in the ocrelizumab treatment arm. The significance of this finding is uncertain because the numbers were small, and there was no clear pattern to suggest a causal relationship to treatment. Moreover, the biological effect of ocrelizumab is nearly identical to that of rituximab, an antibody therapy used for treatment of non-Hodgkin's lymphoma and rheumatoid arthritis in over 4 million persons worldwide that is not associated with an increased risk of malignancy. Proof that ocrelizumab does not fractionally contribute to an overall risk of permissive malignancy will require large, well-controlled patient registries: data from such registries, once they are established, will not be available for several years to provide a definitive answer to this question. Baring the unanswered question about a hypothetical increased risk of permissive malignancy, ocrelizumab appears to offer efficacy that is, similar to that of natalizumab, alemtuzumab or mitoxantrone. Although none of these agents formally have been compared head-to-head, based on cross-trial comparisons, their overall effectiveness compared with all other therapies seems to be in a similar range. What distinguishes ocrelizumab from these other therapies is a markedly better safety profile. As discussed above, natalizumab is associated with a potential high risk of PML in JCV seropositive patients, alemtuzumab causes de novo autoimmune conditions in w40% of treated patients, and mitoxantrone causes cardiomyopathy as well as an unacceptably high risk of leukemia. In contrast to these therapies, ocrelizumab seems far more benign. In relapsing MS patients, should ocrelizumab be used as a first-line therapy? Or should ocrelizumab be reserved as a second-line treatment? Clearly, in patients with PPMS, it is the only approved therapy. However, the clinical trial in patients with PPMS was not representative of the overall PPMS population. In the ocrelizumab trial, the maximum age for participation in the study was 55 years. Study subjects who were younger and had evidence of active inflammatory disease activity (i.e., having gadoliniumDPTA enhancing lesions on brain MRI) were much more likely to benefit from treatment than subject who were older and did not have active MS on baseline brain MRI. Therefore, application of the positive results of the trial in clinical practice for patients with PPMS who are older than 55 years and who experience disability progression in the Cree: J Neuro-Ophthalmol 2018; 38: 251-262 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Bench to Bedside absence of radiographic evidence of active inflammation is challenging. Another clinical challenge is whether the results of the relapsing studies and primary progressive studies can be taken together and be applied to patients with secondary progressive MS. Although the FDA appears to consider patients with SPMS as a relapsing form of MS, third party payers are often less inclined to accept this interpretation and sometimes restrict access to medications approved for relapsing forms of MS to patients with secondary progressive disease. The remarkable results from the ocrelizumab program potentially constitute a major breakthrough in MS therapies because of uncontestable proof of superiority of ocrelizumab over the so-called platform therapy subcutaneous interferon beta-1a in RMS and its designation as the first disease modifying therapy for PPMS. The infrequent administration and generally favorable side effect profile of ocrelizumab make it a candidate for both front-line and second-line therapy. Given that we have no reliable methods for predicting disease course or therapeutic response in MS, the time has come to ask if a "one-size-fits-all" treatment with ocrelizumab should be offered to (nearly) all MS patients? REFERENCES 1. 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