Multiple Sclerosis

Number: 0264

Least Cost Medically Necessary Brands

Extavia

For Aetna commercial plans, Extavia (interferon beta-1b) brand is more costly to Aetna than other alternatives ("least cost alternatives") for certain indications. There is a lack of reliable evidence that Extavia is superior to the least cost alternatives for the medically necessary indications listed below. Therefore, Aetna considers Extavia to be medically necessary for members who have a contraindication, intolerance or ineffective response to the least cost alternatives per criteria below:

Clinically Isolated Syndrome (CIS) and Relapsing forms of Multiple Sclerosis (MS)

Treatment with an adequate trialFootnotes* of two preferred alternatives was ineffective, not toleratedFootnotes**, or is contraindicated. The preferred alternatives are as follows:

Betaseron
Copaxone
Mayzent

Plegridy

For Aetna commercial plans, Plegridy (peginterferon beta-1a) brand is more costly to Aetna than other alternatives ("least cost alternatives") for certain indications. There is a lack of reliable evidence that Plegridy is superior to the least cost alternatives for the medically necessary indications listed below. Therefore, Aetna considers Plegridy to be medically necessary for members who have a contraindication, intolerance or ineffective response to the least cost alternatives per criteria below:

Clinically Isolated Syndrome (CIS) and Relapsing forms of Multiple Sclerosis (MS)

Treatment with an adequate trialFootnotes* of two preferred alternatives was ineffective, not toleratedFootnotes**, or is contraindicated. The preferred alternatives are as follows:

Betaseron
Copaxone, glatiramer, or Glatopa
Mayzent

Lemtrada

For Aetna commercial plans, Lemtrada (alemtuzumab) brand is more costly to Aetna than other brands of targeted immune modulators (“least cost brands of targeted immune modulators”) for certain indications. There is a lack of reliable evidence that Lemtrada is superior to the least cost brands of targeted immune modulators, other than interferons, for the medically necessary indications listed below. Therefore, Aetna considers Lemtrada to be medically necessary for members who have a contraindication, intolerance or ineffective response to the least cost brands of targeted immune modulators per criteria below:

Relapsing forms of Multiple Sclerosis (MS)

For the treatment of clinically isolated syndrome and relapsing forms of MS when an adequate trialFootnotes* of Tysabri AND at least two of the least cost brands listed below was ineffective, not toleratedFootnotes**, or is contraindicated. The least cost brands are as follows:

Aubagio
Betaseron
Gilenya
Copaxone, glatiramer, or Glatopa
Mayzent
Rebif
Tecfidera

* For purposes of this policy, failure of an adequate trial of therapy for multiple sclerosis is defined as follows:

The member has increasing relapses, defined as two or more relapses in a year, or one severe relapse associated with either poor recovery or MRI lesion progression; or
The member has lesion progression by MRI (increased number or volume of gadolinium-enhancing lesions, T2 hyperintense lesions or T1 hypointense lesions); or
The member has worsening disability (sustained worsening of Expanded Disability Status Scale [EDSS] score or neurological examination findings).

Footnotes** Intolerance is defined as intolerable side effects despite optimized management strategies.

Policy

Note: REQUIRES PRECERTIFICATION

Precertification of multiple sclerosis drugs is required of all Aetna participating providers and members in applicable plan designs. For precertification of multiple sclerosis drugs, call (866) 752-7021, (866) 503-0857 (Medicare), or fax (866) 267-3277.

Note: Site of Care Utilization Management Policy applies for alemtuzumab (Lemtrada), natalizumab (Tysabri), ocrelizumab (Ocrevus), and immune globulin. For information on site of service, see Utilization Management Policy on Site of Care for Specialty Drug Infusions.

Intravenous Steroid Treatment
1. Aetna considers intravenous steroid therapy medically necessary for either of the following indications:
  1. Treatment of acute exacerbations of multiple sclerosis (MS) when the acute relapse is characterized by functionally disabling symptoms with documented evidence of neurological impairment (persons who have previously responded in a relapse phase are more likely to do so in the future); or
  2. Use of intermittent pulse dose corticosteroids as a maintenance treatment for MS to delay disease progression. In many cases, members can be treated in the outpatient setting.
2. Aetna considers hospital admission for intravenous steroid therapy medically necessary for the treatment of an acute exacerbation of MS that results in any of the following severe neurological deficits:
  1. Acute cerebral symptoms with severe loss of intellectual capacity; or
  2. Acute epileptic seizure(s); or
  3. Acute fulminant MS characterized by headache, vomiting, convulsions and eventually coma, with severe compromise of functioning of the central nervous system; or
  4. Acute pseudobulbar palsy; or
  5. Acute quadriplegia; or
  6. Acute transverse myelitis (or Brown-Sequard syndrome) with loss of function below the level of a suspected lesion in the spinal cord; or
  7. Acute visual loss.
  An inpatient stay may also be considered medically necessary for persons who have had previous complications from high dose intravenous steroids that justify an inpatient admission.
Outpatient Treatment
1. Relapsing forms of MS. Aetna considers monotherapy with any of the following medications medically necessary for treatment of relapsing forms of MS:
  1. Alemtuzumab (Lemtrada)
  2. Avonex (interferon beta-1a) (see CPB 0404 - Interferons for selection criteria)footNotes¹
  3. Betaseron (interferon beta-1b) (see CPB 0404 - Interferons for selection criteria)
  4. Cladribine (Leustatin, 2-CDA) injection
  5. Copaxone 20 mg (glatiramer acetate, copolymer 1) footNotes¹
  6. Copaxone 40 mg (glatiramer acetate, copolymer 1) footNotes¹
  7. Cyclophosphamide (Cytoxan)
  8. Extavia (interferon beta-1b), (see CPB 0404 - Interferons for selection criteria)
  9. Glatopa 20 mg (glatiramer acetate, copolymer-1)
  10. Imuran (azathioprine)
  11. Mitoxantrone
  12. Plegridy (peginterferon beta-1a) (see CPB 0404 - Interferons for selection criteria)footNotes¹
  13. Rebif (interferon beta-1a) (see CPB 0404 - Interferons for selection criteria)footNotes¹
  14. Rituximab (Rituxan) for the treatment of relapsing MS in persons age 18 years and older (see CPB 0314 - Rituximab (Rituxan) or CPB 0314m - Rituximab (Rituxan) [Medicare])
  15. Tysabri (natalizumab) (see CPB 0751 - Natalizumab (Tysabri) or CPB 0751m - Natalizumab (Tysabri) [Medicare])
  16. Ocrelizumab (Ocrevus) for relapsing multiple sclerosis in persons age 18 years and older footNotes¹ Note: See section on Chronic Progressive MS below for criteria for ocrelizumab in primary progressive multiple sclerosis
  17. For cladribine (Mavenclad) tablets, dalfampridine (Ampyra) tablets, dimethyl fumarate delayed release (Tecfidera) capsules, diroximel fumarate (Vumerity) capsules, fingolimod (Gilenya) capsules, ozanimod (Zeposia) capsules, siponimod (Mayzent) and teriflunomide (Aubagio) tablets, see Commercial Pharmacy CPB on Multiple Sclerosis for selection criteria.footNotes¹.
  Footnotes¹Ocrevus, Plegridy, Tecfidera, Avonex, Copaxone, and Rebif are considered medically necessary for the treatment of relapsing forms of multiple sclerosis (MS) in adults, which includes relapsing-remitting disease, and active secondary progressive disease.
  
  Aetna considers continued treatment with the following drugs medically necessary in members requesting reauthorization for a medically necessary indication who are experiencing disease stability or improvement while receiving treatment: Gilenya, Aubagio, Ocrevus, Copaxone, Glatopa, or glatiramer acetate.
  
  Note: For policy on H.P. Acthar Gel, see CPB 0762 - Repository Corticotropin Injection (H.P. Acthar Gel).
2. Chronic Progressive MS. Aetna considers Mitoxantrone footnotes for the potential for functional cardiac changes^* medically necessary for clinically deteriorating persons with either relapsing or chronic progressive forms of MS.
  
  Aetna considers ocrelizumab (Ocrevus) medically necessary for treatment of adults age 18 years and older with primary progressive MS.
3. Plasma exchange/plasmapheresis is considered medically necessary for individuals with acute, severe neurological deficits caused by MS who have a poor response to treatment with high-dose glucocorticoids.
4. Clinically Isolated Syndrome. Aetna considers monotherapy with any of the following medications medically necessary for treatment of clinically isolated syndrome:
  1. Aubagio (teriflunomide)
  2. Avonex (interferon beta-1a) (see CPB 0404 - Interferons for selection criteria)
  3. Copaxone and Glatopa 20 mg (glatiramer acetate, copolymer 1)
  4. Copaxone and Glatopa 40 mg (glatiramer acetate, copolymer 1)
  5. Gilenya (fingolimod)
  6. Ocrevus (Ocrelizumab) in persons age 18 years and older
  7. Plegridy (peginterferon beta-1a) (see CPB 0404 - Interferons for selection criteria)
  8. Rebif (interferon beta-1a) (see CPB 0404 - Interferons for selection criteria)
  9. Tecfidera (dimethyl fumarate delayed release) capsules (see Commercial Pharmacy CPB on Multiple Sclerosis for selection criteria)
footnotes for the potential for functional cardiac changes^*Note: Because of the potential for functional cardiac changes, the product labeling for Novantrone states that persons receiving Novantrone should have their left ventricular ejection fraction (LVEF) evaluated by echocardiogram or MUGA prior to every dose.

For purpose of this policy, failure of an adequate trial of therapy for multiple sclerosis is defined as follows:
1. The member has increasing relapses (defined as two or more relapses in a year, or one severe relapse associated with either poor recovery or MRI lesion progression); or
2. The member has lesion progression by MRI (increased number or volume of gadolinium-enhancing lesions, T2 hyperintense lesions or T1 hypointense lesions); or
3. The member has worsening disability (sustained worsening of Expanded Disability Status Scale (EDSS) score or neurological examination findings).
Intolerance is defined as intolerable side effects despite optimized management strategies.

Note: Policy requirements for a trial of an injectable drug therapy may be waived for persons who meet diagnostic criteria for needle phobia (see appendix for DSM 5 criteria), if there is documentation of preexisting excessive fear (outside of the particular request being considered) of injections and blood draws with documented attempts at management and psychological counseling, especially if there are associated symptoms (vasovagal syncope, panic attack).
Aetna considers continued treatment with the following drugs medically necessary in members requesting reauthorization for a medically necessary indication and are experiencing disease stability or improvement while receiving treatment: Gilenya, Aubagio, Ocrevus, glatiramer acetate (Copaxone, Glatopa), or Tysabri.
Experimental and Investigational Interventions

Aetna considers the following interventions experimental and investigational for MS:
1. Alpha-interferon
2. Anti-T-cell monoclonal antibodies other than natalizumab (Tysabri, Antegren)
3. Anti-lymphocyte globulin
4. APOE genotyping
5. Balloon angioplasty / balloon venoplasty / venous angioplasty with or without stent placement (chronic cerebrospinal venous insufficiency (CCSVI) treatment)
6. Brainstem auditory evoked response for diagnosing MS
7. Cerebrospinal fluid levels of neurofilament as a biomarker of MS
8. Clemastine fumarate for the treatment of chronic demyelinating injury in MS
9. Cooling garment
10. Cosyntropin (Cortrosyn)
11. Cyclosporine (Sandimmune)
12. Dietary interventions (e.g., gluten-free diets, low fat diets, linoleate supplementation to diet, and dietary regimens with polyunsaturated fatty acids)
13. Electronystagmography (in the absence of vertigo or balance disorder)
14. Erythropoesis stimulating agents (unless criteria are met in CPB 0195 - Erythropoiesis Stimulating Agents or CPB 0195m - Erythropoiesis Stimulating Agents [Medicare])
15. Estrogen receptor beta ligands
16. Ferritin/iron status (blood or CSF) for the diagnosis of MS
17. Functional electrical stimulation (FES) cycling
18. Gamma-interferon
19. gMS^®DX and gMS^®Pro EDSS tests for the diagnosis of MS
20. Hyperbaric oxygen
21. Intravesical vanilloids (e.g., capsaicin and resiniferatoxin) for the treatment of neurogenic lower urinary tract dysfunction in individuals with MS
22. IL-2-toxin
23. IL-10
24. IL-16
25. Interleukin-1 gene polymorphisms testing
26. IVIG for Multiple Sclerosis (relapsing MS and progressive MS) (see CPB 0206 - Parenteral Immunoglobulins or CPB 0206m - Parenteral Immunoglobulins [Medicare])
27. Mesenchymal stem cell therapy
28. Mesenchymal stromal cell-derived neural progenitors
29. Methotrexate
30. MTHFR testing for MS
31. Myelin basic protein peptides
32. Myxovirus resistance protein A (MxA) as a biomarker for MS relapse/treatment response
33. Naltrexone
34. Non-pharmacological interventions (biofeedback, hydrotherapy, hypnosis, reflexology, transcranial direct stimulation, transcranial random noise stimulation, and transcutaneous electrical nerve stimulation) for the treatment of chronic pain in MS
35. Ocrelizumab for the treatment of nonrelapsing secondary progressive MS
36. Ofatumumab
37. Optical coherence tomography for screening of member receiving fingolimod (Gilenya) for macular edema (see CPB 0344 - Optic Nerve and Retinal Imaging Methods)
38. Oral myelin (Myloral)
39. Osteopontin as a biomarker for MS
40. Otoacoustic emissions (in the absence of signs of hearing loss)
41. Photopheresis (see CPB 0241 - Extracorporeal Photochemotherapy (Photopheresis))
42. Plasmapheresis for chronic or secondary progressive MS (maintenance therapy)
43. Procarin (transdermal histamine)
44. Prolactin
45. Pulsed magnetic field therapy
46. PUVA (psoralen ultraviolet light)
47. Retinal nerve scanning for screening/monitoring persons on fingolimod (Gilenya)
48. Ribavirin
49. Serum neurofilament as a marker of neuroaxonal injury in early MS and for monitoring disease activity
50. Sildenafil
51. Statins
52. Stem cell transplantation (see CPB 0606 - Stem Cell Transplant for Autoimmune Diseases and Miscellaneous Indications
53. T-cell receptor therapy
54. T-cell vaccination
55. Total lymphoid irradiation
56. Transcranial brain sonography for predicting disease progression in MS
57. Transforming growth factor (TGF)-beta
58. Tumor necrosis factor antagonists
59. Tympanometry (in the absence of hearing loss).
Aetna considers assays of neutralizing antibodies (NABs) against interferon beta (Betaseron) to be experimental and investigational because its clinical value has not been established.

Aetna considers measurements of hematopoietic stem and progenitor cells counts as a biomarker of responsiveness to natalizumab experimental and investigational because its clinical value has not been established.

Aetna considers determination of the expression of the splice variants of the tumor necrosis factor-related apoptosis inducing ligand (TRAIL) and its receptors as a biomarker of responsiveness to interferon-beta experimental and investigational because its clinical value has not been established.
Concomitant Use

Aetna considers alemtuzumab (Lemtrada), cladribine (Mavenclad), dimethyl fumarate (Tecfidera), fingolimod (Gilenya), glatiramer acetate (Copaxone, Glatopa), interferon beta, natalizumab (Tysabri), ocrelizumab (Ocrevus), siponimod (Mayzent) and/or teriflunomide (Aubagio) used concomitantly with other disease modifying multiple sclerosis agents (Note: Ampyra and Nuedexta are not disease modifying) to be experimental and investigational because the clinical value has not been established.

Aetna considers use of Avonex (interferon beta-1a), Rebif (interferon beta-1a), Betaseron (interferon beta-1b), Extavia (interferon beta-1b) and Plegridy (peginterferon beta-1a) used concomitantly with other disease modifying multiple sclerosis agents (Note: Ampyra and Nuedexta are not disease modifying) to be experimental and investigational because the clinical value has not been established.

Dosing Recommendations

Gilenya (Fingolimod)

Assessments are required prior to initiating Gilenya.

Recommended dosage for adults and pediatric patients (10 years of age and older) weighing more than 40 kg: 0.5 mg orally once-daily, with or without food
Recommended dosage for pediatric patients (10 years of age and above) weighing less than or equal to 40 kg: 0.25 mg orally once-daily, with or without food.

See Full Prescribing information for additional recommendations for monitoring.

Source: Novartis, 2019

Aubagio (teriflunomide)

The recommended dosage is: 7 mg or 14 mg orally once daily, with or without food

Source: Genzyme, 2019

Ocrevus (ocrelizumab)

Hepatitis B virus screening is required before the first dose. Pre-medicate with methylprednisolone (or an equivalent corticosteroid) and an antihistamine (e.g., diphenhydramine) prior to each infusion. Administer Ocrevus by intravenous infusion

The recommended starting dosage 300 mg intravenous infusion, followed two weeks later by a second 300 mg intravenous infusion. Subsequent doses are 600 mg intravenous infusion every 6 months.

Source: Genentech, Inc., 2019

Lemtrada (alemtuzumab)

Initial treatment of 2 courses:

First course: 12 mg/day on 5 consecutive days
Second course: 12 mg/day on 3 consecutive days 12 months after first treatment course

Subsequent treatment courses of 12 mg per day on 3 consecutive days (36 mg total dose) may be administered, as needed, at least 12 months after the last dose of any prior treatment course.

Source: Genzyme, 2019

Background

Multiple sclerosis (MS) is an acquired immune-mediated inflammatory disease characterized by the destruction of myelin sheaths with preservation of axons occurring in multiple anatomic sites in the brain and spinal cord. Its clinical course is variable and unpredictable and exact etiology is unknown, although data suggests that it is an autoimmune disease triggered by a viral infection in genetically susceptible individuals.

Multiple Sclerosis (MS) attacks myelinated axons in the central nervous system (CNS), destroying the myelin and the axons. There are approximately 400,000 people in the United States and 2.1 million people worldwide with MS. Most people with MS are diagnosed between the ages of 20‐50 years old. Though the etiology of MS is unknown, it is hypothesized that MS results when an environmental agent or event (e.g. viral or bacterial infection, exposure to chemical) act in conjunction with a genetic predisposition to immune dysfunction. Risk factors for MS include gender (women 2‐3x increased risk), genetics, age, geography, and ethnic background.

Four disease courses have been identified in multiple sclerosis: clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS).

Clinically Isolated Syndrome (CIS)

CIS is a first episode of neurologic symptoms caused by inflammation and demyelination in the central nervous system. The episode, which by definition must last for at least 24 hours, is characteristic of multiple sclerosis but does not yet meet the criteria for a diagnosis of MS because people who experience a CIS may or may not go on to develop MS. When CIS is accompanied by lesions on a brain MRI (magnetic resonance imaging) that are similar to those seen in MS, the person has a high likelihood of a second episode of neurologic symptoms and diagnosis of relapsing-remitting MS. When CIS is not accompanied by MS-like lesions on a brain MRI, the person has a much lower likelihood of developing MS (National Multiple Sclerosis Society, 2019).

Primary‐progressive MS (PPMS)

Patients experience a slow but nearly continuous worsening of their disease from the onset, with no distinct relapses or remissions. However, there are variations in rates of progression over time, occasional plateaus, and temporary minor improvements. This type of MS is relatively rare occurring in approximately 15% of patients.

Primary-progressive MS (PPMS) can be further characterized at different points in time as either active (with an occasional relapse and/or evidence of new MRI activity), or not active, as well as with progression (evidence of worsening disease with or without relapse, or per MRI) or without progression (National Multiple Sclerosis Society, 2018).

In 2013, medical experts redefined the types of MS. As a result, progressive-relapsing (PRMS) is no longer considered one of the distinct types of MS. People who might have received a diagnosis of PRMS in the past are now considered to have primary progressive MS (PPMS) with active disease. Patients experience a steadily worsening disease from the onset but also have clear acute relapses (attacks or exacerbations), with or without recovery. In contrast to relapsing‐remitting MS, the periods between relapses are characterized by continuing disease progression. This type of MS is relatively rare occurring in approximately 5% of patients.

(National Multiple Sclerosis Society, 2019; Olek, 2016).

Relapsing‐remitting MS (RRMS)

RRMS is the most common disease course and approximately 85% of people with MS are initially diagnosed with RRMS. RRMS is characterized by clearly defined attacks of new or increasing neurologic symptoms. These attackes, also called relapses or exacerbations, are followed by periods of partial or complete recovery (remissions). During remissions, all symptoms may disappear, or some symptoms may continue and become permanent. However, there is no apparent progression of the disease during the periods of remission. At different points in time, RRMS can be further characterized as either active (with relapses and/or evidence of new MRI activity) or not active, as well as worsening (a confirmed increase in disability over a specified period of time following a relapse) or not worsening (National Multiple Sclerosis Society, 2019).

Classical exacerbating-remitting usually begins with the acute or subacute onset of focal neurologic signs and symptoms, typically evolving over 1 to 3 days, stabilizing for a few days, and then improve spontaneously, followed by an onset of new focal symptoms months or years later. On rare occasions, MS has a relatively acute onset with a rapidly progressive course involving multiple areas of the nervous system simultaneously and leading to severe impairment and death within a few weeks or months. In chronic progressive MS, the course is insidious and progressive from the onset, usually occurs in patients greater than 35 years of age, and presents as a chronic myelopathy with slowly or intermittent, progressive symptoms. Neuromyelitis optica (Devic’s syndrome) is a clinical syndrome consisting of both optic neuritis and transverse myelitis, occurring simultaneously or separately by only a brief interval in a patient without prior evidence of MS.

Patients with MS initially present with sensory disturbances in 1 or more limbs, disturbances of balance and gait with ataxia, optic nerve dysfunction with visual loss in 1 eye, diplopia, nystagmus, dysarthria, upper motor neuron spastic weakness, intention tremors, autonomic dysfunction, bladder dysfunction, spastic paraparesis, and retrobulbar neuritis, in various combinations. About 50 % of patients with isolated optic neuritis will develop MS.

The diagnosis of MS remains clinical at present, with demonstration of signs and symptoms spread out in time and space being required. Most patients have initial symptoms which totally resolve only to relapse with progressive residual disability after each exacerbation and significant neurologic dysfunction developing over a period of several years. Less than 1/3 of MS patients have a very benign course with minimal or no disability, and about 10 % have a very malignant course with severe disability within months to a few years.

At onset, about 65 % of patients have a relapsing-remitting form of the disease. These patients have exacerbations with symptoms attributable to central nervous system (CNS) lesions or plaques. The flare-ups usually develop subacutely and resolve over weeks to months. About 15 % of patients have exacerbations similar to the relapsing-remitting disease but less complete recovery that leaves the patients with significant residual disability. This form is referred to as the relapsing-progressive form. Finally, there is the chronic progressive form dominated by spinal cord and cerebellar dysfunction. In about 20 % of patients, the initial symptoms start with this chronic progressive form, whereas, more often, it develops out of the relapsing-remitting disorder over time.

The inflammatory response in the CNS consists predominantly of activated T lymphocytes and macrophages accompanied by a local immune reaction with the secretion of cytokines and the synthesis of oligoclonal immunoglobulin within the CNS. Multiple sclerosis is thought to either be a cell-mediated autoimmune attack against myelin antigens or the presence of a persistent virus or infectious process within the CNS against which the inflammatory response is directed.

Many scattered, discrete areas of demyelination, termed plaques, are the pathologic hallmark of multiple sclerosis. Only limited regeneration of myelin occurs once the myelin sheath is destroyed (shadow plaques). Conduction of nerve impulses along axons denuded of their myelin is slowed or blocked. This loss of conduction is analogous to a segment of electrical wire being stripped of its insulating cover, allowing escape of current and diminishment of its force down the rest of the wire.

The essentials of diagnosis are: episodic symptoms that may include sensory abnormalities, blurred vision, sphincter disturbances, and weakness with or without spasticity; patient is usually under 55 years of age at onset; single pathologic lesion can not explain clinical findings; and multiple foci best demonstrated by magnetic resonance imaging (MRI).

An accurate diagnosis is extremely important because this disorder mimics many diseases of the central nervous system. The clinical history, including a history of at least 2 episodes of neurologic deficit, and physical examination showing objective clinical signs of lesions at more than one site within the CNS, remain of paramount importance in establishing a correct diagnosis. However, the sine qua non of the initial diagnosis is the MRI demonstration that different regions of the white matter of the CNS have been affected by lesions at different times by demonstrating multiple white matter lesions (plaques) which represent a clearly defined patch of demyelination of sheaths of neurons in the CNS signifying areas of slowed or loss conduction leading to symptoms. Diagnosis is confirmed with the aid of a number of procedures. Cerebrospinal fluid (CSF) examination show elevated immunoglobulin G (IgG) and oligoclonal banding (electrophoretic bands which represents fractionations of IgG). Evoked potential testing demonstrates conduction disturbances. The diagnosis of MS rests as much as ever on the considered opinion of the neurologist, based heavily on the clinical features of the patient's illness.

The treatment of MS must be individualized to the patient. Patients with stable disease, mild acute attacks, consisting of minor paresthesias, slight weakness, or incoordination that do not significantly interfere with normal activities require no treatment, as these attacks subside in 1 to 2 weeks without treatment. Symptomatic treatment for spasticity, paresthesias, fatigue, and bowel and bladder difficulties may be required. Patients with progressive MS are treated with immunomodulating therapy, however, unfortunately no therapy has had a significant beneficial effect on the course of progressive MS. Because the clinical examination is a relatively crude indicator to assess the efficacy of treatment, recent studies are using MRI to assess therapeutic benefit.

Early in the disease course, many patient exhibit little neurologic dysfunction and require minimal therapy. Many times their attacks are self-limiting and the main therapy offered is counsel and advise. When intervention is required, therapy is directed toward altering the clinical course with the use of immunosuppressives, or alleviating symptoms (spasticity, fatigue, depression, pain, bladder dysfunction, and cerebellar dysfunction).

Secondary Progressive MS (SPMS)

Secondary progressive MS (SPMS) SPMS follows an initial relapsing-remitting course. Most people who are diagnosed with RRMS will eventually transition from the inflammatory process seen in RRMS to a more steadily progressive phase characterized by nerve damage or loss during and an accumulation of disability during the secondary progressive course (National Multiple Sclerosis Society, 2019).

Steroids

Intravenous steroids are safe and effective in treating acute exacerbations of MS. Its use is directed at the early halting or diminishing of the destructive inflammatory process in the central nervous system, so that neurologic disability doesn't accumulate. For an acute relapse, a course of intravenous corticosteroids is typically given (500 mg to 1 gram of methylprednisolone (Solu-Medrol) over 30 to 60 mins for 3 days). This course can be extended up to 5 days (or to even 10 days) if the attack continues to progress or is slow in improving. Intravenous methylprednisolone is also the usual primary treatment for optic neuritis. The somewhat rapid effect of steroid treatment is based partly by reduction of white matter edema, and somewhat by an alteration of immunological factors. It is unusual in practice to give more than 2 or 3 courses of steroids for the treatment of relapses.

ACTH

An acute relapse of MS may require no treatment if it is mild or does not produce functional decline. However, relapses that cause significant disability are usually treated with a course of intravenous corticosteroids. Studies have shown that corticosteroids or ACTH decrease the length of a clinical relapse of MS, and some studies have shown that corticosteroids are superior to and have fewer side effects than ACTH. It is not unusual to see the onset of a major depressive episode coincident with the first relapse episode, in spite of appropriate patient education as to the nature of the illness and in spite of mild severity of symptoms. The response to steroids is often exhilarating (hypomanic, or even psychotic) followed by the return of severe depressive symptoms once the steroids are discontinued. It is not unusual, therefore, that these patients may require a psychological assessment early on if depressive symptoms persist.

Adrenocorticotropic hormone (ACTH) is secreted by the anterior pituitary and stimulates the adrenal cortex to secrete cortisol, aldosterone, and androgenic hormones. The anti-inflammatory, and possibly the inhibition of antibody production, appear to the effects most relevant to MS. The growth of the use of synthetic glucocorticoids arose from efforts to minimize the many undesirable side effects related to aldosterone and androgen stimulation. Therefore, the use of oral glucocorticoids and the intravenous use of high-dose methylprednisolone has largely supplanted ACTH treatment.

Interferon Beta-1B

The mechanism of action of interferon beta‐1b in patients with multiple sclerosis is unknown. Interferon beta‐1b receptor binding induces the expression of proteins that are responsible for the pleiotropic bioactivities of interferon beta‐1b. A number of these proteins (including neopterin, B2‐microglobulin, MxA protein, and IL‐10) have been measured in blood fractions from Betaseron‐treated patients and Betaseron‐treated healthy volunteers. Immunomodulatory effects of interferon beta‐1b include enhancement of suppressor T cell activity, reduction of pro‐inflammatory cytokine production, down regulation of antigen presentation, and inhibition of lymphocyte trafficking into the central nervous system. It is not known if these effects play an important role in the observed clinical activity of Betaseron in MS.

Interferon beta‐1b is indicated for the treatment of relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations and for those who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis.

Interferon beta‐1b should be used with caution in patients with depression, a condition that is common in people with MS.

Female patients should be cautioned about the abortifacient potential of interferon beta‐1b.

Betaseron was the first disease‐modifying agent to show therapeutic efficacy in MS. Beta interferon (Betaseron) has been demonstrated in controlled trials to reduce the frequency and severity of acute attacks. It has been shown to decrease the number of acute attacks of MS by about 1/3 and to decrease the average severity of attacks so that attacks classified as moderate to severe were reduced by more than 50 %, as well as causing a dramatic reduction in the appearance of new lesions on MRI. Betaseron is available as a lyophilized power containing 0.3 mg of interferon beta‐1b in a single‐use vial.

Extavia contains the same medicinal product as Betaseron. Extavia is available as a lyophilized power containing 0.3 mg of interferon beta‐1b in a single‐use vial.

The recommended dose of interferon beta‐1b is 0.25 mg injected subcutaneously every other day. Generally, members should be started at 0.0625 mg subcutaneously every other day and increased over a six week period to 0.25 mg every other day.

Interferon Beta-1A

Avonex (interferon beta‐1a for intramuscular injection) is indicated for the treatment of relapsing forms of multiple sclerosis to slow the accumulation of physical disability and decrease the incidence of clinical exacerbations and for those who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis. Interferon beta‐1a for intramuscular injection is available as Avonex in a 30 mcg lyophilized powder vial, a 30 mcg prefilled syringe, and a 30mcg single‐use prefilled autoinjector pen. The recommended dosage of Avonex is 30 mcg intramuscularly once weekly. The updated Food and Drug Administration (FDA) approved prescribing labeling for Avonex states that it is indicated for the treatment of clinically isolated syndrome and for the treatment of relapsing forms of multiple sclerosis (MS) in adults. The labeling states relapsing forms of MS includes relapsing-remitting disease, and active secondary progressive disease (Avonex Prescribing Information, 2019)

Interferon beta‐1a should be used with caution in patients with depression or other mood disorders, conditions that are common in patients with MS. Depression, suicidal ideation, and suicide attempts have been reported to occur with increased frequency in patients receiving interferon compounds.

Caution should also be exercised when administering interferon beta‐1a to patients with pre‐existing seizure disorder.

Patients with cardiac disease, such as angina, congestive heart failure, or arrhythmia should be monitored for worsening of their clinical condition during initiation and continued treatment with interferon beta‐1a.

Severe liver injury, including some cases of hepatic failure requiring liver transplantation, has been reported rarely in patients taking interferons. If jaundice or other symptoms of liver dysfunction appear treatment with interfersons should be discontinued immediately due to the potential for rapid progression to liver failure.

Rebif (interferon beta‐1a for subcutaneous injection) is indicated for the treatment of patients with relapsing forms of multiple sclerosis to decrease the frequency of clinical exacerbations and delay the accumulation of physical disability. Interferon beta‐1a for subcutaneous injection is available as Rebif 8.8mcg, 22mcg, and 44mcg in prefilled syringes and autoinjector pens. The recommended dose of Rebif (interferon beta‐1a) is 22 mcg or 44 mcg injected subcutaneously three times a week. The 8.8mcg presentation is used for titration purposes only. Rebif (interferon beta‐1a) should be administered, if possible, at the same time on the same three days. The updated Food and Drug Administration (FDA) approved prescribing labeling for Rebif states that it is indicated for the treatment of clinically isolated syndrome and for the treatment of relapsing forms of multiple sclerosis (MS) in adults. The labeling states relapsing forms of MS includes relapsing-remitting disease, and active secondary progressive disease (Rebif Prescribing Information, 2019)

Plegridy (peginterferon beta‐1a for subcutaneous injection) is an interferon beta indicated for the treatment of patients with relapsing forms of multiple sclerosis. Peginterferon beta‐1a for subcutaneous injection is available as Plegridy in 63mcg, 94mcg, and 125mcg prefilled syringes and single‐use prefilled autoinjector pens. Starter packs contain one each of the lower two strengths. The recommended maintenance dosage of Plegridy is 125mcg injected subcutaneously once every 14 days. The updated Food and Drug Administration (FDA) approved prescribing labeling for Plegridy states that it is indicated for the treatment of clinically isolated syndrome and for the treatment of relapsing forms of multiple sclerosis (MS) in adults. The labeling states relapsing forms of MS includes relapsing-remitting disease, and active secondary progressive disease (Plegridy Prescribing Information, 2019)

Cyclophosphamide

As a result of the current thoughts on the immunological pathogenesis of the disease, immunosuppressive and immunomodulating drugs remain the mainstay of treatment for progressive MS. These drugs are used to prevent relapses and progression, to provide symptomatic treatment of MS, and occasionally for acute flare-ups. There are no large controlled trials of the efficacy of this therapy on acute exacerbations. The immunosuppressive agents currently used are all controversial, with data published supporting and disproving their efficacy. These therapies for acute flare-ups should be reserved for debilitating exacerbations, as patients appear to become resistant to therapy and there is no evidence that the ultimate degree of recovery is altered. A Cochrane review (La Mantia et al, 2007) concluded that the overall effect of cyclophosphamide (administered as intensive schedule) in the treatment of progressive MS does not support its use in clinical practice.

Cladribine

Cladribine (Leustatin) provides immunomodulation through selective targeting of lymphocyte subtypes that is being investigated in the treatment of patients with relapsing remitting MS. Giovannoni et al (2009) presented the results of the CLARITY study, a phase III, randomized, double-blind study to evaluate the safety and efficacy of oral cladribine in relapsing-remitting MS. Relapsing-remitting MS patients were randomized to one of two cladribine regimens or to placebo. Cladribine tablets were administered for 5 days per 28-day treatment course for 2 or 4 consecutive courses during the first 48 weeks and for 2 consecutive courses at the beginning of the second 48 weeks to achieve a total dosage of 3.5 or 5.25 mg/kg. Of the intention-to-treat population (n = 1326) randomized to 5.25 mg/kg (n = 456), 3.5 mg/kg (n = 433), or placebo (n = 437) groups, 89 %, 92 %, and 87 % completed the study, respectively. Cladribine 5.25 and 3.5 mg/kg versus placebo resulted in sigificantly lower annualized relapse rates (the primary study endpoint) (0.15 and 0.14 versus 0.33; relative reduction in annuallized relapse rate 54.5 % and 57.6 % respectively; both p < 0.001). Of subjects receiving cladribine, 78.9 % and 79.7 % of the 5.25 and 3.5 mg/kg groups were relapse free versus 60.9 % of placebo patients (odds ratios: 2.43 and 2.53, respectively; both p < 0.001). Cladribine groups had an approximately 30 % relative reduction in risk of disability progression (hazard ratio; 95 % confidence interval [CI]: 0.69 [0.49 to 0.96] and 0.67 [0.48 to 0.93]; p = 0.026 and p = 0.018; 5.25 mg/kg and 3.5 mg/kg groups versus placebo, respectively). The investigators resported that highly significant reductions in brain lesion activity were seen in all 3 MRI measures: T1-Gd+, active T2, and new combined lesions. The investigators stated that, overall, frequencies of adverse events in the cladribine groups were low and comparable with placebo. The investigators noted that events related to cladribine's mechanism of action, such as lymphopenia, were reported more frequently with cladribine treatment. The investigators concluded that cladribine treatment resulted in significant improvements in clinical and MRI outcomes and was accompanied by a favorable safety and tolerability profile, suggesting that annual short-course treatment with cladribine may provide an important new option in multiple sclerosis therapy.

Mitoxantrone

Novantrone (mitoxantrone for injection) acts in MS by suppressing the activity of T cells, B cells, and macrophages that are thought to lead the attack on the myelin sheath. Novantrone has been approved by the FDA for treatment of both the relapsing-remitting and chronic progressive forms of MS. Because of the potential for functional cardiac changes, the product labeling for Novantrone states that persons receiving Novantrone should have cardiac monitoring. The FDA recommends that the left ventricular ejection fraction (LVEF) should be evaluated by echocardiogram or MUGA prior to every dose administered to patients with MS. Additional doses of Novantrone should not be administered to MS patients who have experienced either a drop in LVEF to below 50 % or a clinically significant reduction in LVEF during Novantrone therapy. The labeling states that patients with MS should not receive a cumulative dose greater than 140 mg/m2.

The use of multiple sclerosis drugs in combination is an active area of research. The primary rationale for polytherapy in multiple sclerosis is that the involved treatments target different mechanisms of the disease and therefore their use is not necessarily exclusive. Synergies, in which one drug potentiates the effect of another are also possible, but there can also be important drawbacks such as antagonizing mechanisms of action or potentiation of deleterious secondary effects. There have been several clinical trials of combined therapy, yet none has shown positive enough effects to merit the consideration as a viable treatment for multiple sclerosis (Milo & Panitch, 2011).

Statins

It is not known whether statins are effective therapy for MS. Birnbaum et al (2008) explored whether high-dose atorvastatin can be administered safely to persons with relapsing-remitting MS taking thrice-weekly, 44 microg dose subcutaneous interferon (IFN) beta-1a. Subjects were randomized in a double-blind fashion to receive either placebo or atorvastatin at dosages of 40 or 80 mg/day for 6 months. Blinded neurological examinations and brain MRI readings were obtained at months 0, 3, 6, and 9. Laboratory blood testing was performed monthly. Main outcome measures were the determination of drug toxicity using blood tests and ECG and determination of MS-related disease activity, either clinical relapses or new or contrast-enhancing lesions on MRI. A total of 26 subjects received at least one dose of study drug. Ten of 17 subjects on either 80 mg or 40 mg of atorvastatin per day had either new or enhancing T2 lesions on MRI or clinical relapses. One of the 9 subjects on placebo had a relapse with active lesions on MRI. Subjects receiving atorvastatin were at greater risk for either clinical or MRI disease activity compared to placebo (p = 0.019). Significant changes in blood tests were noted only for lower cholesterol levels in subjects receiving atorvastatin. The authors concluded that the combination of 40 or 80 mg atorvastatin with thrice-weekly, 44 microg IFN beta-1a in persons with MS resulted in increased MRI and clinical disease activity; caution is suggested in administering this combination.

In an editorial that accompanied the afore-mentioned article, Goldman and Cohen (2008) stated that "there are several ongoing larger studies of statins in MS, both as monotherapy and combined with other medications. Hopefully these studies will clarify whether statins are useful as MS therapy".

Spasticity Treatments

Alleviation of the symptoms of MS becomes necessary, since effective curative therapy is not yet available. Symptomatic treatment provides the means of improving the quality of life of individuals with MS. Oral baclofen commonly is used to treat spasticity, however, a major side effect is increased weakness of the limb with possible negative effects on ambulation. Oral tizanidine can also be used to treat spasticity, where loss of strength appears to be less of a problem. Intrathecal baclofen via an implantable pump has been shown to be very effective in treating severe, intractable spasticity; however, careful selection of patients is mandatory as this is an invasive procedure with a number of potentially dangerous complications (hypotension, respiratory insufficiency, and meningitis). When all forms of medical treatment are insufficient to prevent spasticity-related complications, injection of phenol can be used to perform neurolysis. Tenotomies of fixed contractures can also be useful in extremely disabled patients to allow adequate nursing. Oral clonazepam, hydroxyzine and beta-blockers can be used to treat tremors. Irritative or obstructive bladder symptoms, as a result of spinal lesions causing detrusor hyperreflexia and incomplete bladder emptying, can be treated with oral anticholinergic medication (e.g., oxybutynin) and intermittent self-catheterization. Carbamazepine can be used to treat trigeminal neuralgia, the most common neurologic symptom in multiple sclerosis patients, and bouts of itching, burning sensations, twitching of the face, and a current of electricity flowing the length of their spine.

Hyperbaric Oxygen

Hyperbaric oxygen (HBO) therapy has not been shown to be effective in the treatment of MS. Hyperbaric oxygen therapy, the intermittent inhalation of 100 % oxygen under a pressure greater than 1 atmospheres pressure (atm), is one of many unconventional treatments tried as a possible treatment for MS. It can be administered in either a mono-place or multi-place chamber. The latter accommodates 2 to 14 people and can achieve pressures up to 6 atm. Patients breath 100 % oxygen through a face mask, head hood, or endotracheal tube and can be cared for by medical personnel directly within the chamber. Monoplace chambers treat a single patient in an environment maintained at 100 % oxygen, thus, no mask is required. Possible complications of HBO therapy include barotrauma (ear or sinus trauma, tympanic membrane rupture, pneumothorax, air embolism), oxygen toxicity (central nervous system or pulmonary), fire, reversible visual changes and claustrophobia. Although early uncontrolled clinical trials and anecdotal reports suggested that HBO may be beneficial in the management of MS, more recent controlled studies with larger sample sizes indicate that this modality is not effective in the treatment of this central nervous system disease.

Erythropoietin

Ehrenreich et al (2007) performed an investigator-driven, exploratory open label study (phase I/IIa) in patients with chronic progressive MS. Main study objectives were

evaluating safety of long-term high-dose intravenous recombinant human erythropoietin (rhEPO) treatment in MS, and
collecting first evidence of potential efficacy on clinical outcome parameters.

A total of 8 MS patients: 5 randomly assigned to high-dose (48,000 IU), 3 to low-dose (8,000 IU) rhEPO treatment, and, as disease controls, 2 drug-naïve Parkinson patients (receiving 48,000 IU) were followed over up to 48 weeks: a 6-week lead-in phase, a 12-week treatment phase with weekly EPO, another 12-week treatment phase with bi-weekly EPO, and a 24-week post-treatment phase. Clinical and electrophysiological improvement of motor function, reflected by a reduction in expanded disability status scale, and of cognitive performance was found upon high-dose EPO treatment in MS patients, persisting for 3 to 6 months after cessation of EPO application. In contrast, low-dose EPO MS patients and drug-naïve Parkinson patients did not improve in any of the parameters tested. There were no adverse events, no safety concerns and a surprisingly low need of blood-lettings. The authors concluded that this first pilot study demonstrated the necessity and feasibility of controlled trials using high-dose rhEPO in chronic progressive MS.

Ankle Foot Orthosis (AFOs)

In a cross-sectional study (n = 15), Sheffler and colleagues (2008) examined if an ankle foot orthosis (AFO) would improve gait velocity and tasks of functional ambulation in patients with MS. Subjects experienced dorsiflexion and eversion weakness, and had used a physician-prescribed AFO for more than 3 months. Ambulation was evaluated

without an AFO and
with an AFO.

Outcome measures were the Timed 25-Foot (T25-FW) Walk portion of the Multiple Sclerosis Functional Composite and the 5 trials (floor, carpet, up and go, obstacles, and stairs) of the Modified Emory Functional Ambulation Profile (mEFAP). The mean timed differences on the T25-FW and the 5 components of the mEFAP between the AFO versus no device trials were not statistically significant. The authors concluded that in MS subjects with dorsiflexion and eversion weakness, no statistically significant improvement was found performing timed tasks of functional ambulation with an AFO.

Plasma Exchange

Therapeutic plasmapheresis (also known as platepheresis or plasma exchange) is performed to remove toxic elements from the bloodstream. An intravenous catheter (small tube) is placed into a vein and connected to a machine (cell separator) via plastic tubing. Blood is pumped through the tubing into the machine where it is separated into red blood cells, white blood cells and plasma. The plasma is then discarded while the other components are combined with a plasma substitute and reinfused into the individual.

Plasma exchange has some evidence for the treatment of various stages of MS. Laboratory abnormalities are suggestive that MS is an immune-mediated disease; this is the rational basis of offering plasma exchange. Specifically, it is hypothesized that humoral factors may be involved, as evidenced by the presence of anti-myelin antibodies and non-antibody demyelinating factors in the sera of patients with MS and the presence of circulating autoantibodies. The specific identity of these humoral factors has not yet been identified. Further evidence supporting the use of PE has been its success in other autoimmune diseases. However, available clinical studies, including randomized controlled clinical trials, have not proven that plasma exchange is effective for MS. A systematic review of the literature on plasma exchange for MS (Nicholas and Chataway, 2006) concluded that there is "insufficient evidence to assess plasma exchange in people with acute relapses of multiple sclerosis."

The Multiple Sklerose Therapie Konsensus Gruppe (2006) stated that the monoclonal antibodies provide considerable improvement of treatment for MS, but their use in basic therapy is restricted by their side effect profile. Thus, natalizumab is only approved for monotherapy after basic treatment has failed or for rapidly progressive relapsing-remitting MS. In contrast, long-term data on recombinant beta-interferons and glatiramer acetate (Copaxone) show that even after several years no unexpected side effects occur and that a prolonged therapeutic effect can be assumed which correlates with the dose or frequency of treatment. Recently IFN-beta1b (Betaferon) was approved for prophylactic treatment after the first attack (clinically isolated syndrome, CIS). During treatment with beta-interferons, neutralizing antibodies can emerge with possible loss of effectivity. In contrast, antibodies play no role in treatment with glatiramer acetate. During or after therapy with mitoxantrone, serious side effects (cardiomyopathy, acute myeloid leukemia) appeared in 0.2 to 0.4 % of cases. Plasmapheresis is limited to individual curative attempts in escalating therapy of a severe attack. According to the revised McDonald criteria, the diagnosis of MS can be made as early as the occurrence of the first attack.

Tackenberg et al (2007) stated that the natural course of MS is probably more favorable than previously assumed years ago. Since the introduction of interferons in Germany, the establishment and further development of new diagnostic criteria (McDonald criteria), the causal and symptomatic treatment possibilities and initiation of therapy early in the course of the disease have led to a considerable change in the treatment of MS. Attacks of MS are usually treated with the intravenous administration of high-dosed steroids. When the attack symptoms do not sufficiently subside, plasmapheresis can be considered. For long-term treatment of MS, beta interferon, glatirameracetate and natalizumab are available as basic causal therapy and natalizumab and mitoxantrone are available for escalation therapy. Frequently occurring spasticity, chronic fatigue syndrome, depression, cognitive disturbances, incontinence, pain, ataxia and sexual disorders must be treated symptomatically. Overall, the outpatient treatment of MS is complex and should be carried out with close co-operation between the family doctor, neurological practices and outpatient departments specialized in treating MS.

Oh et al (2008) noted that B-cells and humoral immunity have been implicated in the pathogenesis of MS. The most common pattern of demyelinating pathology in MS is associated with the deposition of antibodies and the activation of complement, as well as T-cells and macrophages. Plasmapheresis has been found to be an efficient therapeutic approach in patients with this type of pathological lesion.

Matsui (2008) noted that Japanese patients with relapsing-remitting MS (RRMS) consists of 2 groups. One is opticospinal form (OSMS), in which major neurological symptoms derive from optic neuritis and myelitis, and the other is conventional form (CMS) that shares similar genetical and clinical features with western type of MS. Patients with OSMS tend to experience disease relapses more frequently with the resultant severer neurological deficit than CMS ones. Both OSMS and CMS patients are treated with intravenous high-dose methylprednisolone in acute exacerbations, and plasmapheresis may be considered for those who do not respond to repeated intravenous steroids. For prevention of disease relapse, interferon-beta is effective; however, patients with long spinal cord lesion extending over 3 vertebral segments should be followed-up with caution, as this finding indicates a risk of treatment failure.

Ohji and Nomura (2008) discussed steroid pulse therapy and apheresis therapy indicated for the treatment of MS. In the basic treatment course for MS, steroid pulse therapy is a first-line treatment for RR-MS in the course of the exacerbation, and apheresis therapy is performed in refractory cases. Treatment strategies for chronic progressive MS are not to be established. Steroid pulse therapy has been established as a treatment for MS in the active phase through randomized controlled trials (RCT). Apheresis therapy includes plasmapheresis and cytapheresis, and plasmapheresis includes plasma exchange (PE) and immunoadsorption plasmapheresis (IAPP). Plasma exchange and IAPP are performed for MS treatment. The former has been established as a useful treatment for active phase MS. The efficacy of IAPP has been frequently reported, but no reports have been based on RCT.

Schroder et al (2009) stated that apheresis is a general term that describes removal of abnormal blood constituents by extracorporeal blood purification methods. To date, therapeutic PE is the most common apheresis procedure. Here, plasma is separated from corpuscular blood constituents and replaced with a substitution fluid. In contrast to immunoadsorption, PE is a non-specific treatment modality with elimination of the entire plasma. The therapeutic effect is based on the removal of circulating, pathogenic immune factors including autoantibodies. Currently, PE is used for treatment of several immune-mediated neurological disorders. While first experiences relate to acute life-threatening conditions, such as treatment of Guillain-Barré syndrome or myasthenic crisis, therapeutic success was also shown in chronic diseases where immunosuppressive therapy is often required for long-term management. Plasma exchange has been applied successfully in chronic inflammatory demyelinating polyneuropathy, paraproteinemic polyneuropathy, stiff person syndrome, and may also be tried in several diseases of paraneoplastic origin. In recent years, PE was also established as an escalation therapy for steroid-unresponsive relapses of MS, and thus has gained more widespread attention.

Olek (2009) stated that PE may be beneficial in patients with acute central nervous system (CNS) inflammatory demyelinating disease who do not respond to glucocorticoid therapy. In the only formally reported clinical trial, 22 patients with CNS demyelinating disease (12 with MS) were randomly assigned to either active PE or sham treatment, with a total of 7 treatments, given every 2 days over 14 days. Moderate or greater improvement in neurologic disability occurred during 8 of 19 (42 %) courses of active treatment compared with 1 of 17 (6 %) courses of sham treatment. Improvement occurred early in the course of treatment and was sustained on follow-up. However, 4 of the patients who responded to the active treatment experienced new attacks of demyelination during 6 months of follow-up. Given these data, the author suggested treatment with PE for patients with acute, severe neurologic deficits caused by MS who have a poor response to treatment with high-dose glucocorticoids.

In January 2011, the American Academy of Neurology (AAN) published a new guideline on PP in neurologic disorders (Cortese et al, 2011). It states that PP/PE can be used as second-line treatment of steroid-resistant exacerbations in relapsing forms of MS. Moreover, PP is established as ineffective and should not be offered for chronic or secondary progressive MS.

Neutralizing Antibodies Against Interferon Beta

Assays of neutralizing antibodies (NABs) against interferon beta (Betaseron) have not been proven to be useful in MS. About 1/3 of individuals develop NABs against interferon beta. A number of laboratories have developed assays for these NABs (e.g., MxA Assay (Berlex Laboratories), NabFeron (Athena Diagnostics)). However, according to the peer-reviewed medical literature, the clinical utility of these assays has not been established. Evidence-based guidelines on MS from the American Academy of Neurology (Goodin et al, 2002) state: "The rate of neutralizing antibody (NAb) production is probably less with IFN-1a treatment than with IFN-1b treatment, and the presence of NAb may be associated with a reduction in clinical effectiveness of IFN treatment. The existing data are, however, ambiguous in this regard, and the clinical utility of measuring NAb in an individual on IFN therapy is uncertain."

While the European Federation of Neurological Societies Task Force on anti-IFN-beta antibodies in multiple sclerosis (Sorensen et al, 2005) recommended that tests for the presence of NABs should be performed in all patients at 12 and 24 months of interferon beta therapy, the consensus statement from an international conference on the significance of NABs to interferon beta during treatment of MS (Hartung et al, 2005) stated that “an international standardized assay for NAb is needed; and all patients with MS who receive IFN-beta therapy should be evaluated for the presence of Nab. Moreover, guidelines on how to manage NAb-positive patients should be developed to optimize IFN-beta therapy; these treatment guidelines should be based on the results of well-controlled clinical studies …. An international standardized assay will facilitate direct comparison of NAb titers amongst studies and will provide further information regarding the immunogenicity of the various types of IFN-beta products and how NAb impact clinical efficacy".

Antonelli and colleagues (2005) stated that “[t]here is a lack of substantial information on the biological/immunological phenomenon of neutralising antibodies in vivo development. Nevertheless, sufficient experimental data are available to provide a rationale for monitoring the presence of anti-IFN antibodies in patients treated with IFN beta. A standardised quantitative assay to detect antibody to IFNs must be agreed. Only when results can be compared, both in terms of the qualitative presence and quantitative measurement of antibodies, will it be possible to monitor fully the ability of antibodies to cause a relapse during treatment. Although there is increasing evidence to indicate that the development of antibodies to IFN beta may be associated with a failure of the beneficial effects of the therapy, the use of the seropositivity for neutralising antibodies to IFN beta as the only surrogate marker for clinical and therapeutic decision-making is questionable”. Also, guidelines on MS from the Association of British Neurologists (2001) stated that monitoring neutralizing antibodies for beta interferon is not necessary.

Noronha (2007) noted that an effect on relapse rates and imaging parameters was noted in patients who tested positive for NAbs, but disability measures were unaffected or showed a trend toward improvement. Patients who developed NAbs during IFN-beta1a therapy tended to remain NAb+, whereas those who developed NAbs during IFN-beta1b therapy tended to revert to NAb- over time. The author stated that the prevalence of NAbs in suboptimal responders does not support a causal relationship of suboptimal responses to the development of NAbs. Thus, decisions to alter treatment should be rendered by clinicians based on the clinical state of the patient.

Natalizumab

Natalizumab (Tysabri, Biogen-Idec, Cambridge, MA) is indicated for persons with relapsing forms of MS who have not responded adequately, or can not tolerate, other treatments for MS. Tysabri was initially approved by the FDA in November 2004, but was withdrawn from the market in February 2005, after 3 patients in the drug's clinical trials developed progressive multifocal leukoencephalopathy (PML). Two of the cases were fatal.

The FDA allowed a clinical trial of natalizumab to resume in February 2006, following a re-examination of the patients who had participated in the previous clinical trials, confirming that there were no additional cases of PML. To decrease the possibility of patients developing PML in the future, the manufacturer, Biogen-IDEC, submitted to the FDA a Risk Management Plan, called the TOUCH Prescribing Program, to ensure safe use of the product. The FDA has determined that natalizumab can be made available under the TOUCH Prescribing Program with the following main features:

Natalizumab will only be administered to patients who are enrolled in the program.
Patients on natalizumab are to be evaluated at 3 and 6 months after the first infusion and every 6 months after that, and their status will be reported regularly to the product’s manufacturer.
Prior to initiating the therapy, health care professionals are to obtain the patient's MRI scan to help differentiate potential future MS symptoms from PML.
The drug will only be prescribed, distributed, and infused by prescribers, infusion centers, and pharmacies registered with the program.

To date, 7 cases of PML have been identified in users of natalizumab. The FDA has reviewed information pertaining to the most recent cases and continues to recommend that natalizumab monotherapy may confer a lower risk of PML than when natalizumab is used together with other immunomodulatory medications.

An assessment of natalizumab for MS by the American Academy of Neurology included the following recommendations.

Because of the possibility that natalizumab therapy may be responsible for the increased risk of PML [progressive multifocal leukoencephalopathy], it is recommended that natalizumab be reserved for use in selected patients with relapsing remitting disease who have failed other therapies either through continued disease activity or medication intolerance, or who have a particularly aggressive initial disease course. This recommendation is very similar to that of the FDA.
Similarly, because combination therapy with IFN-beta and natalizumab may increase the risk of PML, it should not be used. There are also no data to support the use of natalizumab combined with other disease-modifying agents as compared to natalizumab alone. The use of natalizumab in combination with agents not inducing immune suppression should be reserved for properly controlled and monitored clinical trials.

Apolipoprotein E Polymorphisms

Shi et al (2008) stated that while the role of apolipoprotein E (APOE) polymorphism has been well recognized in cognitive neurodegenerative disorders, its role in MS is less clear. Studies indicated that 40 % to 60 % of patients with MS have evidence of cognitive impairment. These researchers examined if there is an association between APOE epsilon 4 and cognitive deficits in MS. They performed a standardized battery of neuropsychological tests investigating the 4 cognitive domains commonly impaired in MS and assessed the association of the presence of APOE epsilon 4 with cognition in these patients. A strong association was found between the presence of APOE epsilon 4 and cognitive deficits in patients with MS, especially in the domains of learning and memory. This association was strongest in the youngest cohort (aged 31 to 40 years) of patients with MS. The authors concluded that APOE epsilon 4 is significantly associated with cognitive impairment in patients with MS. However, the modest effects do not justify APOE genotyping of patients with MS in clinical practice.

Guerrero et al (2008) evaluated if there is any correlation between APOE genotype and severity according to Multiple Sclerosis Severity Score (MSSS). This study included 82 patients with disease duration of at least 2 years. These investigators collected data concerning demographic and clinical variables including age of onset, disease duration, Expanded Disability Status Scale (EDSS) score and the total number of relapses. They determined the latency to EDSS scores of 4.0 and 6.0; calculated progression index (PI) and relapse rate (RR); and ascertained MSSS in the global MSSS table. The authors reported that 4 patients heterozygous for the E2 allele and 16 for the E4 allele. No patient was homozygous for E2 or E4. RR (p = 0.017 with 95 % CI] 0.005 to 0.57) and PI (p = 0.016 with 95 % CI: 0.004 to 0.38) were significantly lower in E4 carriers. Multiple Sclerosis Severity Score was not associated with carriership of E2 or E4. The authors concluded that these findings show no effect of the APOE genotype on the severity of MS measured by MSSS, as a recently published meta-analysis has noticed. Thus, the data do not support a role for APOE in MS severity.

Transcranial Ultrasound

An early neurodegenerative affection of subcortical gray matter has been suggested in patients with MS. Transcranial sonography (TCS) shows hyper-echogenic lesions of substantia nigra (SN) and basal ganglia, thought to reflect iron accumulation, in a number of primary neurodegenerative diseases. Walter and colleagues (2009) examined if TCS can also display deep gray matter lesions in patients with MS and whether sonographic findings relate to severity and progression of MS. These researchers prospectively studied 75 patients with different courses of MS and 55 age-matched healthy subjects clinically and with TCS. Additionally, 23 patients had 1.5-T MRI at the time of TCS. Disease progression was assessed clinically 2 years after TCS. Abnormal hyper-echogenicity of SN, lenticular nucleus (LN), caudate nucleus, and thalamus was found in 41 %, 54 %, 40 %, and 8 % of the patients with MS, with similar frequency in patients with relapsing-remitting and primary or secondary progressive MS if corrected for disease duration, but only in 13 %, 13 %, 5 % (each, p < 0.001), and none (p = 0.028) of the control subjects. Hyperechogenicity of SN and LN correlated with more pronounced MRI T2 hypointensity, thought to reflect iron deposition. Larger bilateral SN echogenic area was related to higher rate of disease progression, whereas small SN echogenic area (SN hypo-echogenicity) predicted a disease course without further progression within 2 years. The authors concluded that neurodegenerative disease-like deep gray matter lesions can be frequently detected by TCS in patients with MS. They stated that these findings suggest that TCS shows changes of brain iron metabolism which correlate with future progress of MS. These investigators also noted that future studies are needed to determine if patients with MS with or without LN hyper-echogenecity represent different pathological sub-types that may benefit from different treatment strategies.

In an editorial that accompanied the afore-mentioned article, Pirko and Zivadinov (2009) stated that there are a number of issues that raise questions regarding the universal applicability of this technique:

increased echo-genecity of gray matter nuclei was reported only in 40 to 50 % of MS cases at baseline;
the echo-genecity was evaluated by means of a 3-grade visual scale as opposed to an objective calculated numerical intensity measure; and
investigator agreement -- a human factor that may introduce bias -- was needed to ascertain if the TCS findings are really abnormal; and
blinding in this study was practically impossible.

The editorialists stated that to validate these TCS findings, large case-control studies are needed.

Chronic Cerebrospinal Venous Insufficiency Treatment / Balloon Venoplasty

Chronic cerebrospinal venous insufficiency (CCSVI) has been suggested to be a possible cause of MS. If the presumed mechanism of venous stasis-related parenchymal iron deposition and neurodegeneration were true, then up-regulation of intra-thecal iron transport proteins may be expected. Worthington et al (2010) carried out a cross-sectional (n = 1,408) and longitudinal (n = 29) study on CSF ferritin levels in patients with MS and a range of neurological disorders. Pathologic (greater than 12 ng/ml) CSF ferritin levels were observed in 4 % of the control patients (median 4 ng/ml), 91 % of patients with superficial siderosis (75 ng/ml), 73 % of patients with a subarachnoid hemorrhage (59 ng/ml), 10 % of patients with relapsing-remitting MS (5 ng/ml), 11 % of patients with primary progressive MS (6 ng/ml), 23 % of patients with secondary progressive MS (5 ng/ml), and 23 % of patients with meningoencephalitis (5 ng/ml). In MS, there was no significant change of CSF ferritin levels over the 3-year follow-up period. The authors concluded that these findings do not support an etiologic role for CCSVI-related parenchymal iron deposition in MS.

Doepp et al (2011) stated that CCSVI was proposed as the causal trigger for developing MS. However, current data are contradictory and a gold standard for venous flow assessment is missing. These investigators compared structural magnetic resonance venography (MRV) and dynamic extracranial color-coded duplex sonography (ECCS) in a cohort of patients with MS. They enrolled 40 patients (44 +/- 10 years). All underwent contrast-enhanced MRV for assessment of internal jugular vein (IJV) and azygos vein (AV) narrowing, graded into 3 groups: 0 % to 50 %, 51 % to 80 %, and greater than 80 %. Extracranial color-coded duplex sonography (analysis of blood flow direction, cross-sectional area (CSA), and blood volume flow (BVF) in both IJV and vertebral veins (VV) occurred in the supine and upright body position. Magnetic resonance venography identified 1 AV narrowing. Internal jugular vein analysis yielded 12 patients for group 1 (30 %), 19 patients for group 2 (48 %), and 9 patients for group 3 (22 %). By ECCS criteria, 4 patients (10 %) presented with venous drainage abnormalities. Jugular BVF was different only between groups 1 and 3 (616 +/- 133 versus 381 +/- 213 ml/min, p = 0.02). No other parameters in supine position and none of the parameters in the upright body position, apart from the IJV-BVF decrease in groups 1 and 3 (479 +/- 172 versus 231 +/- 144 ml/min, p = 0.01), were different. The authors concluded that these ECCS data contradict the postulated 100 % prevalence of CCSVI criteria in MS. Magnetic resonance venography seems more sensitive to detect IJV narrowing compared to ECCS. A measurable hemodynamic effect only exists in vessel narrowings greater than 80 %. They stated that these combined data argue against a causal relationship of venous narrowing and MS, favoring the rejection of the CCSVI hypothesis and underline the plea to all clinicians to omit any intervention to remove "stenosis" by dilatation or stent implantation.

Zecca and Gobbi (2011) stated that the so called "CCSVI theory" has recently emerged, supporting the concept of cerebrospinal venous drainage impairment as the cause of MS. Since the first publication on this topic with a claimed 100 % specificity and sensitivity of the condition for MS diagnosis, CCSVI theory has generated a scientific and mass media debate with a great hope for the miracle of a new possible endovascular treatment of MS ("liberation procedure"). These investigators critically summarized the available evidence on CCSVI discussing inconsistent and incomplete replication of the original results by different groups, methodological limits and potential therapeutic implications. The authors concluded that the available data are insufficient to establish conclusively a clear relationship between MS and CCSVI and do not support the role of CCSVI as the primary cause of MS. They stated that until credible scientific evidence replicates the original results, any proposed invasive treatments of CCSVI should be discouraged.

The Canadian Agency for Drugs and Technologies in Health's update on the "Investigation of Chronic Cerebrospinal Venous Insufficiency for the Treatment of Multiple Sclerosis" (CADTH, 2012) states that "[i]t is not yet established whether chronic cerebrospinal venous insufficiency (CCSVI) contributes to MS disease activity, and there have been conflicting data as to the frequency of this condition in people with MS. Recent results from a large clinical trial suggest that CCSVI may be the result of the disease rather than a cause. It is hoped that findings from ongoing studies will provide clarity regarding the need for pan-Canadian therapeutic clinical trials".

Endovascular procedures such as angioplasty with or without stenting has been studied for the treatment of patients with MS. Kostecki et al (2011) prospectively evaluated the mid-term results (6 month follow-up) of the endovascular treatment in patients with CCSVI and MS. A total of 36 patients with confirmed MS and CCSVI underwent endovascular treatment by the means of the uni- or bi-lateral jugular vein angioplasty with optional stent placement. All the patients completed 6 month follow-up. Their MS-related disability status and quality of life were evaluated 1, 3 and 6 months post-operatively by means of the following scales: Expanded Disability Status Scale (EDSS), Multiple Sclerosis Impact Scale (MSIS-29), Epworth Sleepiness Scale (ESS), Heat Intolerance scale (HIS) and Fatigue Severity Scale (FSS). For patency and re-stenosis rate assessment, the control ultrasound (US) duplex Doppler examination was used. Six months after the procedure, re-stenosis in post-percutaneous transluminal angioplasty (PTA) jugular veins was found in 33 % of cases. Among 17 patients who underwent stent implantation into the jugular vein, re-stenosis or partial in-stent thrombosis was identified in 55 % of the cases. At the 6 month follow-up appointment, there was no significant improvement in the EDSS or the ESS. The endovascular treatment of the CCSVI improved the quality of life according to the MSIS-29 scale but only up to 3 months after the procedure (with no differences in the 6 month follow-up assessment). Six months after the jugular vein angioplasty (with or without stent placement), a statistically significant improvement was observed only in the FSS and the HIS. The authors concluded that endovascular treatment in patients with MS and concomitant CCSVI did not have an influence on the patient's neurological condition; however, in the mid-term follow-up, an improvement in some quality-of-life parameters was observed.

Kipshidze et al (2011) noted that in recent observational studies performed on patients from distinctive gene pools, the prevalence of CCSVI in MS ranged from 56 % to 100 %. Endovascular treatment (PTA) with or without stenting of CCSVI was reported to be feasible with a minor complication rate. In 4 patients with different forms of MS, venography was performed that revealed stenosis of the proximal region of the jugular vein (right or left). Percutaneous transluminal balloon angioplasty was performed in all patients. There were no complications and mean stenosis was reduced after PTA from 59.75 % to 36.75 %. Follow-up included clinical observations and MRI. In all the cases these researchers observed positive remission of the disease, the first ever documented case of MRI index improvement. PTA seems to be an effective treatment for patients with CCVI and MS. The authors concluded that randomized studies are needed to establish the effectiveness of this new treatment for MS.

A position statement by the Society of Interventional Radiology, endorsed by the Canadian Interventional Radiology Association (Vedantham et al, 2010) considered the published literature to be inconclusive on whether CCSVI is a clinically important factor in the development and/or progression of MS, and on whether balloon angioplasty and/or stent placement are clinically effective in patients with MS.

The Ontario Health Technology Advisory Committee (2010) stated that "OHTAC has undertaken a preliminary evidence review of the safety and effectiveness of endovascular treatments for chronic cerebrospinal venous insufficiency in patients with multiple sclerosis and is unable to make any recommendation at this time due to the paucity of available evidence. OHTAC regards this treatment as experimental at this time".

The National Institute for Health and Clinical Excellence (2012) has concluded: "Current evidence on the efficacy of percutaneous venoplasty for chronic cerebrospinal venous insufficiency (CCSVI) for multiple sclerosis (MS) is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research."

Reekers et al (2011) stated that "many interventional radiologists, who are directly approached by MS patients, contact the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) for advice. Worldwide, several centers are actively promoting and performing balloon dilatation, with or without stenting, for CCSVI. Thus far, no trial data are available, and there is currently no randomized controlled trial (RCT) in progress. Therefore, the basis for this new treatment rests on anecdotal evidence and successful testimonies by patients on the Internet. CIRSE believes that this is not a sound basis on which to offer a new treatment, which could have possible procedure-related complications, to an often desperate patient population".

In a pilot, case-control study, Zamboni et al (2012) examined if PTA of duplex-detected lesions, of the internal jugular and/or azygous veins, was safe, burdened by a significant re-stenosis rate, and whether there was any evidence that treatment reduced MS disease activity. These researchers studied 15 patients with relapsing-remitting MS and duplex-detected CCSVI. Eight patients had PTA in addition to medical therapy (immediate treatment group (ITG)), whereas 7 had treatment with PTA after 6 months of medical therapy alone (delayed treatment group (DTG)). No adverse events occurred. At 1 year, there was a re-stenosis rate of 27 %. Overall, PTA was followed by a significant improvement in functional score compared with baseline (p < 0.02). The annualized relapse rate was 0.12 % in the ITG compared with 0.66 % in the DTG (p = NS). Magnetic resonance imaging blindly demonstrates a trend for fewer T2 lesions in the ITG (p = 0.081), corresponding to a 10 % decrease in the ITG compared with a 23 % increase in the DTG over the first 6 months of the study. The authors concluded that the findings of this study further confirmed the safety of PTA treatment in patients with CCSVI associated with MS. They stated that the results, despite the significant rate of re-stenosis, are encouraging and warrant a larger multi-center double-blinded, randomized study.

Siddiqui et al (2014) reported the results of the investigation of safety and effectiveness of venous angioplasty in patients with MS with findings of extra-cranial venous anomalies, considered hallmarks of CCSVI, in a 2-phase study. Phase 1 was an open-label safety study (10 patients); phase 2 was sham-controlled, randomized, and double-blind (10 sham procedure, 9 treated). All study patients fulfilled venous hemodynamic screening criteria indicative of CCSVI. Assessment was at 1, 3, and 6 months post-procedure with MRI, clinical, and hemodynamic outcomes. Primary end-points were safety at 24 hours and 1 month, venous outflow restoration greater than 75 % at 1 month, and effect of angioplasty on new lesion activity and relapse rate over 6 months. Secondary end-points included changes in disability, brain volume, cognitive tests, and quality of life. No peri-operative complications were noted; however, 1 patient with history of syncope was diagnosed with episodic bradycardia requiring placement of a pacemaker before discharge. Doppler evidence-based venous hemodynamic insufficiency severity score (VHISS) was reduced greater than 75 % compared to baseline in phase 1 (at 1 month) but not phase 2. In phase 2, higher MRI activity (cumulative number of new contrast-enhancing lesions [19 versus 3, p = 0.062] and new T2 lesions [17 versus 3, p = 0.066]) and relapse activity (4 versus 1, p = 0.389) were identified as non-significant trends in the treated versus sham arm over 6 months. Using analysis of co-variance, significant cumulative new T2 lesions were related to larger VHISS decrease (p = 0.028) and angioplasty (p = 0.01) over the follow-up. No differences in other end-points were detected. The authors concluded that venous angioplasty is not an effective treatment for MS over the short-term and may exacerbate underlying disease activity. This is a Class I study demonstrating that clinical and imaging outcomes are no better or worse in patients with MS identified with venous outflow restriction who receive venous angioplasty compared to sham controls who do not receive angioplasty.

In an editorial that accompanied the afore-mention study, Bourdette and Cohen (2014) stated that “Clinical trials of venous angioplasty for MS are placing participants at risk of complications without a reasonable hope of benefit”.

On May 10, 2012, the FDA issued an alert on potential dangers of an experimental procedure sometimes called “liberation therapy” or the “liberation procedure” to treat CCSVI. The alert noted that some researchers believe that CCSVI, which is characterized by a narrowing (stenosis) of veins in the neck and chest, may cause MS or may contribute to the progression of the disease by impairing blood drainage from the brain and upper spinal cord. However, studies exploring a link between MS and CCSVI are inconclusive, and the criteria used to diagnose CCSVI have not been adequately established. The experimental procedure uses balloon angioplasty devices or stents to widen narrowed veins in the chest and neck. However, the FDA has learned of death, stroke, detachment and migration of the stents, damage to the treated vein, blood clots, cranial nerve damage and abdominal bleeding associated with the experimental procedure. Balloon angioplasty devices and stents have not been approved by the FDA for use in treating CCSVI. The FDA also is notifying physicians and clinical investigators who are planning or conducting clinical trials using medical devices to treat CCSVI that they must comply with FDA regulations for investigational devices. Any procedures conducted are considered significant risk clinical studies and require FDA approval, called an investigational device exemption. In February 2012, the FDA sent a warning letter to an investigator who was conducting a clinical study of CCSVI treatment without the necessary approval. The investigator voluntarily closed the study. The FDA stated that it will continue to monitor reports of adverse events associated with “liberation therapy” or the “liberation procedure” and keep the public informed as new safety information becomes available.

In a Cochrane review, van Zuuren et al (2012) evaluated the effects of percutaneous transluminal angioplasty for the treatment of CCSVI in people with MS. These investigators searched the following databases up to June 2012: The Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialized Register, CENTRAL in The Cochrane Library 2012, Issue 5, MEDLINE (from 1946), EMBASE (from 1974), and reference lists of articles. They also searched several online trials registries for ongoing trials; RCTs assessing the effects of percutaneous transluminal angioplasty in adults with MS that have been diagnosed to have CCSVI were selected for analysis. The searches retrieved 159 references, 6 of which were to ongoing trials. Based on assessment of the title or abstract, or both, the authors excluded all of the studies, with the exception of 1 that was evaluated following examination of the full text report. However, this study also did not meet the inclusion criteria and was subsequently excluded. No RCTs met the inclusion criteria. The authors concluded that there is currently no high-level evidence to support or refute the safety or effectiveness of percutaneous transluminal angioplasty for treatment of CCSVI in people with MS. They stated that clinical practice should be guided by evidence supported by well-designed RCTs: closure of some of the gaps in the evidence may be feasible at the time of completion of the 6 ongoing clinical trials.

In a randomized, double-blind, sham-controlled, phase-II clinical trial, Traboulsee and colleagues (2018) determined the safety and efficacy of balloon versus sham venoplasty of narrowing of the extra-cranial jugular and azygos veins in MS. Patients with relapsing or progressive MS were screened using clinical and US criteria. After confirmation of greater than 50 % narrowing by venography, participants were randomized 1:1 to receive balloon or sham venoplasty of all stenoses and were followed for 48 weeks. Participants and research staff were blinded to intervention allocation. The primary safety outcome was the number of adverse events (AEs) during 48 weeks. The primary efficacy outcome was the change from baseline to week 48 in the patient-reported outcome MS Quality of Life–54 (MSQOL-54) questionnaire. Standardized clinical and MRI outcomes were also evaluated. A total of 104 subjects were randomized (55 sham; 49 venoplasty) and 103 completed 48 weeks of follow-up; 23 sham and 21 venoplasty participants reported at least 1 AE; 1 sham (2 %) and 5 (10 %) venoplasty participants had a serious AE. The mean improvement in MSQOL-54 physical score was +1.3 (sham) and +1.4 (venoplasty) (p = 0.95); MSQOL-54 mental score was +1.2 (sham) and −0.8 (venoplasty) (p = 0.55). The authors concluded that these findings did not support the continued use of venoplasty of extra-cranial jugular and/or azygous venous narrowing to improve patient-reported outcomes, chronic MS symptoms, or the disease course of MS.

In an editorial that accompanied the afore-mentioned study, Friedemann and Wattjes (2018) stated that “This study is another and hopefully the final milestone of evidence that the CCSVI theory in MS is flat wrong in terms of disease pathophysiology and for therapeutic interventions. Given the high requirements for MS therapeutics to be approved by regulatory authorities and the broad spectrum of available MS drugs with Class I evidence in terms of efficacy, treatment strategies related to the CCSVI concept should be absolutely disregarded. After the aforementioned first Canadian multicenter, case-control study published in 2013, we thought that this was the “final curtain”. Obviously, the Canadian study group has now given us a valuable encore presentation. However, there ought not to be further shouts of “encore”. We do not need more data on this wrong and misleading CCSVI concept. There are other much more relevant and burning research questions that need our attention and allocation of resources and funding”.

Myxovirus Resistance Protein A

van der Voort and colleagues (2010) determined if myxovirus resistance protein A (MxA) mRNA is related to clinical disease activity in MS. Baseline MxA mRNA levels were measured in a prospective cohort of 116 untreated patients with early MS and were related to clinical relapses and MRI at baseline and at follow-up. Low levels of MxA mRNA were associated with the occurrence of relapses (p = 0.002) and contrast-enhancing lesions (CELs) on baseline MRI (p = 0.045). In addition, high baseline MxA mRNA levels were related to a longer time to a first new relapse (hazard ratio [HR]: 0.59; 95 % CI: 0.35 to 1.00; p = 0.044). Adding the absence of CELs to high MxA mRNA, the predictive value increased (HR: 0.35; 95 % CI: 0.17 to 0.74; p = 0.006), clearly showing a cumulative value for combining both factors. The authors concluded that MxA mRNA is related to clinical exacerbations, the number of CELs on MRI, and is indicative for the time to a subsequent relapse. They stated that if confirmed (by larger studies), MxA mRNA has potential as a biomarker for clinical disease activity in MS.

gMS^®Pro EDSS Test

The gMS^®Pro EDSS Test is a panel of biomarkers specific to identifying patients who will progress towards higher EDSS scores despite treatment. It was developed to help physicians identify which patients with clinically isolated syndrome (CIS) or newly diagnosed MS will have a higher likelihood of progressing towards meaningful disabilities despite treatment. Physicians may want to consider more aggressive treatment for these patients. In addition, the gMS^®Pro EDSS test is targeted for use for diagnosed MS patients and potential MS patients who have had their first neurological event and will be starting therapeutic treatment for MS. However, there is a lack of evidence regtarding the clinical value of this test.

Neurofilament Heavy Chain Protein

Kuhle et al (2011) examined if CSF levels of neurofilament heavy chain protein (NfH(SMI35)) correlate with disability, disease activity, or specific stages of MS. An electrochemiluminescence immunoassay was used to retrospectively measure NfH(SMI35) in CSF of patients with clinically isolated syndrome (CIS) (n = 63), RRMS (n = 39), secondary progressive multiple sclerosis (SPMS) (n = 25), primary progressive multiple sclerosis (PPMS) (n = 23), or controls (n = 73). Cell count and CSF levels of immunoglobulin and albumin were also measured. CSF levels of NfH(SMI35) increased with age in controls (r(s) = 0.50, p < 0.0001) and CIS (r(s) = 0.50, p < 0.0001); this effect was less pronounced in RRMS (r(s) = 0.35, p = 0.027) and absent in SPMS/PPMS. After age correction, NfH(SMI35) levels were found to be higher in all disease stages compared to control. Relapses were associated with higher CSF NfH(SMI35) values compared with stable disease. NfH(SMI35) levels correlated with EDSS scores in patients with CIS and RRMS (r(s) = 0.33, p = 0.001), and during relapse (r(s) = 0.35, p = 0.01); the correlation was most prominent in RRMS during relapse (r(s) = 0.54, p = 0.01). This was not the case for any of the other CSF markers examined. The authors concluded that neuronal loss is a feature of aging, and the age-dependent increase of CSF NfH(SMI35) suggests that this loss accelerates over time. For MS, increased NfH(SMI35) levels reflect the super-imposed presence of further neurodegenerative processes. Evaluation of NfH(SMI35) levels is likely to provide a useful surrogate for measuring the rate of neurodegeneration in MS. Furthermore, the dissociation of NfH(SMI35) levels with biomarkers of inflammation suggests that the mechanisms responsible for their production are at least partly independent. One major drawback of this study was the use of EDSS to measure disability; it is imprecise and not a good overall measure of MS. More work is needed for CSF levels of neurofilament to become a useful biomarker for MS.

In an editorial that accompanied the afore-mentioned study, Giovannoni and Nath (2011) stated that "[e]levated CSF Nf is a simple indicator of axonal damage, and is predictive of severity and poor recovery from acute attacks and the development of long-term disability in patients with MS. We would encourage the MS community to take these observations on board and to insist on the inclusion of this valuable biomarker in all future clinical trials".

Prolactin

Zhornitsky et al (2013) noted that MS is more common among women than men; and MS often goes into remission during pregnancy, when prolactin (PRL) levels are known to be high. In an animal model of demyelination, PRL promoted myelin repair, suggesting it has potential as a re-myelinating therapy in MS. I n this systematic review, these investigators examined the known associations between PRL and MS, in order to elucidate its potential role in the pathophysiology and treatment of MS. A systematic search was performed in the electronic databases PubMed and EMBASE, using the keywords "prolactin" AND "multiple sclerosis". The inclusion criteria were met by 23 studies. These studies suggested that elevated PRL may be more common in MS patients than in controls. Hyper-prolactinemia may also be associated with clinical relapse in MS, especially among patients with hypothalamic lesions or optic neuritis; however, it is unknown if this is a cause or consequence of a relapse. The authors concluded that overall most people with MS have normal PRL levels; and the impact of PRL on MS outcomes remains unclear.

Interleukin-1

Huang et al (2013) stated that dysregulated levels of interleukin-1 (IL-1) were observed in patients with MS. Previous studies have provided conflicting evidence implicating the IL-1 gene polymorphisms in MS risk. These investigators performed a meta-analysis of 16 case-control studies involving 3,482 cases and 3,528 controls to evaluate this association. No association was found between the IL-1α -889 (rs1800587), IL-1α +4,845 (rs17561), IL-1β -511 (rs16944), IL-1β +3,953 (rs1143634), IL-1ra variable number tandem repeat (VNTR) polymorphisms and MS risk. However, in subgroup analyses for the IL-1ra VNTR polymorphism, these researchers found that individuals carrying the 2 allele had a 32 % increased risk for bout-onset MS (relapsing remitting and secondary progressive MS) when compared to the LL homozygotes (OR = 1.32, 95 % CI: 1.06 to 1.66, p (z) = 0.014). The authors concluded that common variants in the IL-1 region are not associated with MS risk but these findings suggested that the IL-1ra VNTR polymorphism might be associated with bout-onset MS subtype.

MTHFR

There are inconsistent reports of an association between methylenetetrahydrofolate reductase (MTHFR) mutations and MS, but no established clinical utility of such testing. Currently, there are no studies demonstrating that manipulation of diet and vitamins in persons with this mutation can either prevent or delay progression of MS.

Alatab et al (2011) stated that both genetic and inflammatory factors are suspected in the etiology of MS. Of genetic factors, the MTHFR C677T polymorphism has been associated with increased levels of plasma homocysteine, a neuronal excitotoxic amino acid. Sclerotic patients also have elevated levels of plasma and CSF homocysteine. In this study, the association between C677T polymorphism and MS was tested by recruiting 230 healthy and 194 multiple sclerotic age- and gender-matched patients. The MTHFR C677T polymorphism and the serum levels of inflammatory mediators IL-1β, tumor necrosis factor- alpha (TNF-α), and C-reactive protein (CRP) were measured. The levels of TNFα, CRP, and IL-1β were significantly higher in sclerotic patients. T allele was 1.7 times more present in this group. In patient's group, the levels of all inflammatory mediators were higher in T/T compared to 2 other genotypes. Evaluation of the age of onset of disease revealed that subjects with T allele developed the MS disease, almost 4 years sooner than other genotype. The authors concluded that having T allele of C677T in MS might be accompanied with higher levels of serum inflammatory mediators and a vulnerability to earlier age of onset of disease. Moreover, they stated that further studies are needed to elucidate the underlying mechanisms.

Fekih Mrissa et al (2013) stated that MS is a chronic neurological disease characterized by CNS inflammation and demyelination of nerve axons. These researchers investigated a possible association between the methylenetetrahydrofolate reductase (MTHFR) gene and MS in Tunisian patients. The genotyping of 2 missense variants of the MTHFR gene, C677T and A1298C was performed in 80 MS patients and 200 healthy controls. No significant differences were found in the frequency of the MTHFR C677T polymorphism between MS patients and healthy controls. However, the genotype prevalence of the missense variant MTHFR A1298C was significantly different between patients and controls (A/C: 55 % versus 7 %, p<10(-3); C/C: 13.75 % versus 0 %, p < 10(-3), respectively). The authors concluded that although these preliminary findings suggested no association between the MTHFR C677T variants and MS, there is evidence to suggest a significant association between the MTHFR A1298C polymorphisms and MS.

Ineichen et al (2014) noted that MTHFR is necessary for the synthesis of methionine and S-adenosylmethionine, which is necessary for CNS (re-)myelination. The MTHFR variant c.1298A>C was associated with the development of RRMS in a German population. These researchers examined if further genetic variants of methionine metabolism are associated with the development or the clinical course of RRMS. Therefore, genomic DNA of 147 serial German RRMS patients and 147 matched healthy controls was genotyped for 5 polymorphic variants of methionine metabolism. Statistical analyses were performed using multi-variate binary and linear regression analyses. They showed that the insertion allele of cystathionine beta-synthase (CBS) c.844_855ins68bp and the G-allele of reduced folate carrier 1 (RFC1) c.80G>A were associated with an earlier age of onset of MS, suggesting gene-dose effects (median age of onset in years: 25-26-32; standardized regression coefficient beta: 0.216; p = 0.030, and 29-31-35 years; beta: 0.282; p = 0.005, respectively). The authors concluded that mutant variants of CBS and RFC1 may be associated with the age of RRMS onset. They stated that since methionine metabolism can be manipulated by supplementation of vitamins and amino acids, these data provided a rationale for novel ideas of preventive and therapeutic strategies in RRMS.

Furthermore, UpToDate reviews on “Diagnosis of multiple sclerosis in adults” (Olek, 2014a), “Clinical features of multiple sclerosis in adults” (Olek, 2014b), and “Treatment of relapsing-remitting multiple sclerosis in adults” (Olek, 2014 c), and “Pathogenesis and epidemiology of multiple sclerosis” (Olek, 2014 d) do not mention the use of MTHFR testing.

IVIG

IVIG (immune globulin) is a sterile, non‐pyrogenic solution of globulins containing many antibodies normally present in adult human blood. It is officially designated in the United States as IGIV but is commonly referred to as IVIG.

An UpToDate review on “Treatment of progressive multiple sclerosis in adults” (Olek, 2014e) states that “Few clinical trials have studied intravenous immune globulin (IVIG) in progressive forms of MS, and these have shown little or no benefit …. Based primarily on the latter study, treatment with IVIG for progressive MS cannot be recommended”.

An UpToDate review on "Disease-modifying treatment of relapsing-remitting multiple sclerosis in adults" (Olek and Mowry, 2019) states although data are equivocal, there is no compelling evidence that intravenous immune globulin (IVIG) is effective for patients with RRMS. Some, but not all early clinical trials reported beneficial effects for IVIG in RRMS. However, these trials generally involved small numbers of patients, lacked complete data on clinical and MRI outcomes, or used questionable methodology. A later multicenter placebo-controlled trial of 127 patients with RRMS found that IVIG treatment conferred no benefit for reducing relapses or new lesions on MRI.

Rituximab

In a phase II, double-blind, 48-week clinical trial involving 104 patients with relapsing–remitting MS, Hauser et al (2008) assigned 69 patients to receive 1,000 mg of intravenous rituximab and 35 patients to receive placebo on days 1 and 15. The primary end point was the total count of gadolinium-enhancing lesions detected on MRI scans of the brain at weeks 12, 16, 20, and 24. Clinical outcomes included safety, the proportion of patients who had relapses, and the annualized rate of relapse. As compared with patients who received placebo, patients who received rituximab had reduced counts of total gadolinium-enhancing lesions at weeks 12, 16, 20, and 24 (p < 0.001) and of total new gadolinium-enhancing lesions over the same period (p < 0.001); and these results were sustained for 48 weeks (p < 0.001). As compared with patients in the placebo group, the proportion of patients in the rituximab group with relapses was significantly reduced at week 24 (14.5 % versus 34.3 %, p = 0.02) and week 48 (20.3 % versus 40.0 %, p = 0.04). More patients in the rituximab group than in the placebo group had adverse events within 24 hours after the first infusion, most of which were mild-to-moderate events; after the second infusion, the numbers of events were similar in the 2 groups. The authors concluded that a single course of rituximab reduced inflammatory brain lesions and clinical relapses for 48 weeks. However, the authors noted that this phase II study was not designed to evaluate long-term safety or to detect uncommon adverse events. They stated that the safety and effectiveness of rituximab for the treatment of MS need to be validated by larger and longer-term controlled studies. MacFarland (2008) noted that a phase II clinical trial leaves many questions unanswered including the duration of the treatment effect, the effect of progression of disability, and most importantly the types of adverse events that may occur at low frequency. Issues of long-term safety of rituximab must still be addressed, given reports to the FDA of progressive multi-focal leukoencephalopathy in patients with lupus who were treated with rituximab.

In a Cochrane review, He and colleagues (2013) evaluated the safety and effectiveness of rituximab, as monotherapy or combination therapy, versus placebo or approved disease-modifying drugs (DMDs) (IFN-β, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab) to reduce disease activity for people with RRMS. The Trials Search coordinator searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (August 9, 2013). These investigators checked the references in identified trials and manually searched the reports (2004 to August 2013) from neurological associations and MS societies in Europe and America. They also communicated with researchers who were participating in trials on rituximab and contacted Genentech, BiogenIdec and Roche. All randomized, double-blind, controlled parallel group clinical trials with a length of follow-up equal to or greater than 1 year evaluating rituximab, as monotherapy or combination therapy, versus placebo or approved DMDs for patients with RRMS without restrictions regarding dosage, administration frequency and duration of treatment were selected for analysis. These researchers used the standard methodological procedures of The Cochrane Collaboration. Two review authors independently assessed trial quality and extracted data. Disagreements were discussed and resolved by consensus among the review authors. Principal investigators of included studies were contacted for additional data or confirmation of data. One trial involving 104 adult RRMS patients with an entry score less than or equal to 5.0 on the EDSS and at least 1 relapse during the preceding year was included. This trial evaluated rituximab as monotherapy versus placebo, with a single course of 1,000 mg intravenous rituximab (on day 1 and day 15). A significant attrition bias was found at week 48 (24.0 %). Patients receiving rituximab had a significant reduction in total number of gadolinium-enhancing lesions at week 24 (mean number 0.5 versus 5.5; relative reduction 91 %) and in annualized rate of relapse at week 24 (0.37 versus 0.84); but not at week 48 (0.37 versus 0.72). Disability progression was not included as an outcome in this trial. More patients in the rituximab group had adverse events within the 24 hours after the first infusion (78.3 % versus 40.0 %), such as chills, headache, nausea, pyrexia, pruritus, fatigue, throat irritation, pharyngo-laryngeal pain, and most were mild-to-moderate events (92.6 %). The most common infection-associated adverse events (greater than 10 % in the rituximab group) were nasopharyngitis, upper respiratory tract infections, urinary tract infections and sinusitis. Among them, only urinary tract infections (14.5 % versus 8.6 %) and sinusitis (13.0 % versus 8.6 %) were more common in the rituximab group. One ongoing trial was identified. The authors concluded that there is insufficient evidence to support the use of rituximab as a disease-modifying therapy for RRMS because only 1 RCT was included. The quality of the study was limited due to high attrition bias, the small number of participants, and short follow-up. The beneficial effects of rituximab for RRMS remain inconclusive. However, short-term treatment with a single course of rituximab was safe for most patients with RRMS. Mild-to-moderate infusion-associated adverse events were common, as well as nasopharyngitis, upper respiratory tract infections, urinary tract infections and sinusitis. These researchers stated that the potential benefits of rituximab for treating RRMS need to be evaluated in large-scale studies that are of high quality along with long-term safety.

Furthermore, an UpToDate review on “Treatment of relapsing-remitting multiple sclerosis in adults” (Olek, 2014c) states that “In a preliminary randomized trial of 104 adult patients with RRMS, treatment with intravenous rituximab (1000 mg) given on days 1 and 15 was associated with a significant reduction in both total and new gadolinium-enhancing lesions on brain MRI at 24 weeks when compared with placebo. In addition, rituximab treatment was associated with a significant reduction in the proportion of patients who had a clinical relapse by week 24. While these results are promising, further clinical trials are needed to establish the long-term effectiveness and safety of rituximab for RRMS. Rare cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients treated with rituximab. However, it is unknown if rituximab increases the risk of PML, since rituximab is often used to treat patients who have an underlying risk factor for PML”.

Ocrelizumab

Ocrelizumab is a humanized monoclonal antibody that selectively targets CD20-positive B cells, which are thought to be a key contributors to myelin (nerve cell insulation and support) and axonal (nerve cell) damage. This nerve cell damage can lead to disability in people with multiple sclerosis. Based on preclinical studies, ocrelizumab binds to CD20 cell surface proteins expressed on certain B cells, but not on stem cells or plasma cells, and therefore important functions of the immune system may be preserved. The U.S. Food and Drug Administration (FDA) approved ocrelizumab (Ocrevus) for both relapsing and primary progressive forms of multiple sclerosis. The updated Food and Drug Administration (FDA) approved prescribing labeling for Ocrevus states that it is indicated for the treatment of clinically isolated syndrome and for the treatment of relapsing forms of multiple sclerosis (MS) in adults. The labeling states relapsing forms of MS includes relapsing-remitting disease, and active secondary progressive disease (Ocrevus Prescribing Information, 2019).

In two identical RMS Phase III studies (OPERA I and OPERA II), ocrelizumab demonstrated superior efficacy on the three major markers of disease activity by reducing relapses per year, slowing the worsening of disability and significantly reducing MRI lesions compared with high-dose interferon beta-1a (Rebif) over the two-year controlled treatment period. Hauser, et al. (2017) examined the effectiveness of ocrelizumab compared to interferon beta-1a in persons with relapsing multiple sclerosis. In two identical phase 3 trials, investigators randomly assigned 821 and 835 patients with relapsing multiple sclerosis to receive intravenous ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 μg three times weekly for 96 weeks. Key eligibility criteria included an age of 18 to 55 years; a diagnosis of multiple sclerosis (according to the 2010 revised McDonald criteria); an Expanded Disability Status Scale (EDSS) score of 0 to 5.5 at screening (scores range from 0 to 10.0, with higher scores indicating a greater degree of disability); at least two documented clinical relapses within the previous 2 years or one clinical relapse within the year before screening; magneticresonance imaging (MRI) of the brain showing abnormalities consistent with multiple sclerosis; and no neurologic worsening for at least 30 days before both screening and baseline (day 1 trial visit). The key exclusion criteria were a diagnosis of primary progressive multiple sclerosis, previous treatment with any B-cell–targeted therapy or other immunosuppressive medication, and a disease duration of more than 10 years in combination with an EDSS score of 2.0 or less at screening. The primary end point was the annualized relapse rate. The annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P<0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P<0.001). In prespecified pooled analyses, the percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.81; P<0.001), as was the percentage of patients with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; hazard ratio, 0.60; 95% CI, 0.43 to 0.84; P=0.003). The mean number of gadolinium-enhancing lesions per T1-weighted magnetic resonance scan was 0.02 with ocrelizumab versus 0.29 with interferon beta-1a in trial 1 (94% lower number of lesions with ocrelizumab, P<0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions, P<0.001). The change in the Multiple Sclerosis Functional Composite score (a composite measure of walking speed, upper-limb movements, and cognition; for this z score, negative values indicate worsening and positive values indicate improvement) significantly favored ocrelizumab over interferon beta-1a in trial 2 (0.28 vs.0.17, P=0.004) but not in trial 1 (0.21 vs. 0.17, P=0.33). Infusion-related reactions occurred in 34.3% of the patients treated with ocrelizumab. Serious infection occurred in 1.3% of the patients treated with ocrelizumab and in 2.9% of those treated with interferon beta-1a. Neoplasms occurred in 0.5% of the patients treated with ocrelizumab and in 0.2% of those treated with interferon beta-1a. The authors concluded that, among patients with relapsing multiple sclerosis, ocrelizumab was associated with lower rates of disease activity and progression than interferon beta-1a over a period of 96 weeks. The investigators stated that larger and longer studies of the safety of ocrelizumab are required.

Commenting on the studies by Hauser, et al., Naismith (2017) stated: "Early safety appears favorable, but long-term studies and postmarketing surveillance are necessary. Pending FDA approval, this appears to be a promising option for patients needing to switch treatment owing to disease activity and for patients presenting with more concerning prognostic features."

In a separate PPMS Phase III study (ORATORIO), ocrelizumab slowed disability progression and reduced signs of disease activity in the brain (MRI lesions) compared with placebo with a median follow-up of three years. Montalban, et al. (2017) studied ocrelizumab,in the primary progressive form of the multiple sclerosis. In a phase 3 trial, investigators randomly assigned 732 patients with primary progressive multiple sclerosis in a 2:1 ratio to receive intravenous ocrelizumab (600 mg) or placebo every 24 weeks for at least 120 weeks and until a prespecified number of confirmed disability progression events had occurred. Key eligibility criteria were an age of 18 to 55 years, a diagnosis of primary progressive multiple sclerosis (according to the 2005 revised McDonald criteria), a score on the Expanded Disability Status Scale (EDSS) of 3.0 to 6.5 at screening (range, 0 to 10.0, with higher scores indicating greater disability), a score on the pyramidal functions component of the Functional Systems Scale of at least 2 (range, 0 to 6, with higher scores indicating greater disability), a duration of multiple sclerosis symptoms of less than 15 years in patients with an EDSS score of more than 5.0 at screening or less than 10 years in patients with an EDSS score of 5.0 or less at screening, and a documented history or the presence at screening of an elevated IgG index or at least one IgG oligoclonal band detected in the cerebrospinal fluid. Key exclusion criteria were a history of relapsing–remitting, secondary progressive, or progressive relapsing multiple sclerosis; contraindications to magnetic resonance imaging (MRI); contraindications to or unacceptable side effects from oral or intravenous glucocorticoids; and previous treatment with B-cell–targeted therapies and other immunosuppressive medications, as defined in the protocol. The primary end point was the percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis. The percentage of patients with 12-week confirmed disability progression was 32.9% with ocrelizumab versus 39.3% with placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.59 to 0.98; P=0.03). The percentage of patients with 24-week confirmed disability progression was 29.6% with ocrelizumab versus 35.7% with placebo (hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.04). By week 120, performance on the timed 25-foot walk worsened by 38.9% with ocrelizumab versus 55.1% with placebo (P=0.04); the total volume of brain lesions on T2-weighted magnetic resonance imaging (MRI) decreased by 3.4% with ocrelizumab and increased by 7.4% with placebo (P<0.001); and the percentage of brain-volume loss was 0.90% with ocrelizumab versus 1.09% with placebo (P=0.02). There was no significant difference in the change in the Physical Component Summary score of the 36-Item Short-Form Health Survey. Infusion-related reactions, upper respiratory tract infections, and oral herpes infections were more frequent with ocrelizumab than with placebo. Neoplasms occurred in 2.3% of patients who received ocrelizumab and in 0.8% of patients who received placebo; there was no clinically significant difference between groups in the rates of serious adverse events and serious infections. The investigators concluded that, among patients with primary progressive multiple sclerosis, ocrelizumab was associated with lower rates of clinical and MRI progression than placebo. The investigators stated that extended observation is required to determine the long-term safety and efficacy of ocrelizumab.

Commenting on the study by Montalban, et al., Naismith (2017) stated: "One third of patients still progressed while taking ocrelizumab, so clinicians should balance optimism with expectations when discussing this treatment with patients. Patients who are older than 55, wheelchair bound, and with disease duration >15 years were not studied; benefits in that population remain unknown. To assess the risk for neoplasms and infectious complications, long-term evaluation of data from clinical trial populations and postmarketing investigations will be needed. For patients with PPMS who fit study criteria, treatment at this time seems recommendable, pending FDA approval."

An accompanying editorial (Calabresi, 2017) noted that "Although ocrelizumab offers promise for patients with primary progressive multiple sclerosis, who are desperately in need of a therapy, side effects must also be considered. Agents that target the immune system often result in some degree of immune suppression, potentially rendering the host susceptible to infections and impaired immune surveillance of new cancer cells, which could increase the risk of neoplasms. Although the dreaded complication of other drugs for multiple sclerosis, infection with JC virus causing progressive multifocal leukoencephalopathy, has not been seen with B-cell depletion in multiple sclerosis to date, there does appear to be a higher-than-normal risk of herpes reactivation and of neoplasms, especially breast cancer. These side effects will need to be studied in future trials and in phase 4 monitoring in the community to understand the extent of the risk. Clinicians are urged to carefully consider which patients might benefit the most from ocrelizumab and to stay vigilant with regard to monitoring for side effects that could be managed effectively if detected early."

The most common side effects associated with ocrelizumab in all Phase III studies included infusion reactions and upper respiratory tract infections, which were mostly mild to moderate in severity.

Ocrelizumab is administered by intravenous infusion every six months. The first dose is given as two 300 mg infusions given two weeks apart. Subsequent doses are given as single 600 mg infusions.

Do not receive ocrelizumab if you are a patient that has an active hepatitis B virus (HBV) infection. Do not receive ocrelizumab if you are a patient that has had a life threatening allergic reaction to ocrelizumab. Patients should tell their healthcare provider if they have had an allergic reaction to ocrelizumab or any of its ingredients in the past.

Ocrelizumab can cause serious side effects, including:

Infusion reactions

Ocrelizumab can cause infusion reactions that can be serious and require a patient to be hospitalized. A patient will be monitored during the infusion and for at least 1 hour after each infusion of ocrelizumab for signs and symptoms of an infusion reaction. Patients should tell their healthcare provider or nurse if they get any of these symptoms: itchy skin, rash, hives, tiredness, coughing or wheezing, trouble breathing, throat irritation or pain, feeling faint, fever, redness on the face (flushing), nausea, headache, swelling of the throat, dizziness, shortness of breath, fatigue, fast heart beat. These infusion reactions can happen for up to 24 hours after the infusion. It is important that patients call their healthcare provider right away if they get any of the signs or symptoms listed above after each infusion. If a patient gets infusion reactions, the healthcare provider may need to stop or slow down the rate of the infusion.
Infection

Ocrelizumab increases a patient’s risk of getting upper respiratory tract infections, lower respiratory tract infections, skin infections, and herpes infections. Patients should tell their healthcare provider if they have an infection or have any of the following signs of infection including fever, chills, a cough that does not go away, or signs of herpes (such as cold sores, shingles, or genital sores). These signs can happen during treatment or after a patient has received their last dose of ocrelizumab. If a patient has an active infection, their healthcare provider should delay treatment with ocrelizumab until the infection is gone.
Progressive Multifocal Leukoencephalopathy (PML):

Although no cases have been seen with ocrelizumab treatment, PML may happen with ocrelizumab. PML is a rare brain infection that usually leads to death or severe disability. Patients should tell their healthcare provider right away if they have any new or worsening neurologic signs or symptoms. These may include problems with thinking, balance, eyesight, weakness on one side of the body, strength, or using arms or legs.
Hepatitis B virus (HBV) reactivation

Before starting treatment with ocrelizumab, a patient’s healthcare provider will do blood tests to check for hepatitis B viral infection. If a patient has ever had hepatitis B virus infection, the hepatitis B virus may become active again during or after treatment with ocrelizumab. Hepatitis B virus reactivation may cause serious liver problems including liver failure or death. A healthcare provider will monitor a patient if they are at risk for hepatitis B virus reactivation during treatment and after they stop receiving ocrelizumab.
Weakened immune system

Ocrelizumab taken before or after other medicines that weaken the immune system could increase a patient’s risk of getting infections.
Before receiving ocrelizumab, patients should tell their healthcare provider about all of their medical conditions, including if they
- have ever taken, take, or plan to take medicines that affect the immune system, or other treatments for MS;
- have ever had hepatitis B or are a carrier of the hepatitis B virus; have had a recent vaccination or are scheduled to receive any vaccinations. A patient should receive any required vaccines at least 6 weeks before they start treatment with ocrelizumab. A patient should not receive certain vaccines (called ‘live’ or ‘live attenuated’ vaccines) while being treated with ocrelizumab and until their healthcare provider tells them that their immune system is no longer weakened.
- are pregnant, think that they might be pregnant, or plan to become pregnant. It is not known if ocrelizumab will harm an unborn baby. Patients should use birth control (contraception) during treatment with ocrelizumab and for 6 months after the last infusion of ocrelizumab.
- are breastfeeding or plan to breastfeed. It is not known if ocrelizumab passes into the breast milk. Patients should talk to their healthcare provider about the best way to feed their baby if the patient takes ocrelizumab.

Ocrelizumab may cause serious side effects, including risk of cancers (malignancies) including breast cancer. Patients should follow their healthcare provider’s recommendations about standard screening guidelines for breast cancer. Most common side effects include infusion reactions and infections.

Alemtuzumab

The FDA has approved alemtuzumab (Lemtrada) for the treatment of patients with relapsing forms of multiple sclerosis (MS) (Genzyme, 2014). Because of its safety profile, the FDA labeling states that use of Lemtrada should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS.

Alemtuzumab is a monoclonal antibody that targets CD52, a protein abundant on T and B cells (Genzyme, 2014). Circulating T and B cells are thought to be responsible for the damaging inflammatory process in MS. The precise mechanism by which alemtuzumab exerts its therapetuc efffects in multiple sclerosis is unknown but is presumed to involve binding to CD52, a cell surface antigen present on T and B lymphocytes, and on natural killer cells, monocytes and macrophages. Cell surface binding to T and B lymphocytes results in antibody dependent cellular cytolysis and complement mediated lysis. Alemtuzumab depletes circulating T and B lymphocytes after each treatment course. Lymphocyte counts then increase over time with a reconstitution of the lymphocyte population that varies for the different lymphocyte subtypes.

The FDA approval of alemtuzumab is based on two pivotal randomized Phase III open-label rater-blinded studies comparing treatment with alemtuzumab to high-dose subcutaneous interferon beta-1a (Rebif) in patients with relapsing remitting MS who were either new to treatment (CARE-MS I) or who had relapsed while on prior therapy (CARE-MS II) (Genzyme, 2014).

In CARE-MS I, alemtuzumab was significantly more effective than interferon beta-1a at reducing annualized relapse rate (0.18 for alemtuzumab and 0.39 for interferon beta-1a (p<0.0001) (Genzyme, 2014; Cohen, et al., 2012). The difference observed in proportion of patients with disability progression at year two did not reach statistical significance (8 percent for alemtuzumab and 11 percent for interferon beta 1-a (p=0.22)). The percent of patients remaining relapse-free at year two for alemtuzumab was 78 percent versus 59 percent for interferon beta-1a (p<0.0001). The percent change in T2 lesion volume from baseline did not reach statistical significance (-9.3 for alemtuzumab and -6.5 for interferon beta 1-a, p=0.31).

In CARE-MS II, alemtuzumab was significantly more effective than interferon beta-1a at reducing annualized relapse rates (0.26 for alemtuzumab and 0.52 for interferon beta 1-a, p<0.0001) (Genzyme, 2014; Coles, et al., 2012). The proportion of patients with confirmed six-month disability progression was significantly lower for alemtuzumab (13 percent for alemtuzumab versus 21 percent for interferon beta 1-a, p=0.0084). The percent of patients remaining relapse-free at year two for alemtuzumab was 65 percent versus 47 percent for interferon beta-1a (p<0.0001). The percent change in T2 lesion volume from baseline did not reach statistical significance (-1.3 for alemtuzumab and -1.2 for interferon beta 1-a, p=0.14).

The FDA-approved labeling of Lemtrada includes a boxed warning noting a risk of serious, sometimes fatal autoimmune conditions, serious and life-threatening infusion reactions and also noting alemtuzumab may cause an increased risk of malignancies including thyroid cancer, melanoma and lymphoproliferative disorders (Genzyme, 2014). Lemtrada is contraindicated in patients with Human Immunodeficiency Virus (HIV) infection.

Lemtrada is only available through the Lemtrada REMS (Risk Evaluation and Mitigation Strategy) restricted distribution program (Genzyme, 2014). This program has been developed to ensure that access to Lemtrada is only through certified prescribers, healthcare facilities and specialty pharmacies and to also ensure that patients are enrolled in the REMS program. The program is intended to help educate healthcare providers and patients on the serious risks associated with alemtuzumab and the appropriate periodic monitoring required to support the detection of these risks for 48 months after the last infusion. The REMS is based on a developmental risk management program that was used in the Phase 2 and Phase 3 trials and allowed for early detection and management of some of the serious risks associated with alemtuzumab.

Lemtrada (alemtuzumab) is available as 12mg/1.2 ml single-use vials. Alemtuzumab for multiple sclerosis has a dosing and administration schedule of two annual treatment courses (Genzyme, 2014). The first treatment course is administered via intravenous infusion on five consecutive days, and the second course is administered on three consecutive days, 12 months later.

The recommended dosage of Lemtrada (alemtuzumab) is 12 mg/day administered by intravenous infusion for 2 treatment courses:

First treatment course: 12 mg/day on 5 consecutive days (60 mg total dose).
Second treatment course: 12 mg/day on 3 consecutive days (36 mg total dose) administered 12 months after the first treatment course.

The product labeling does not indicate more than two infusion courses.

The most common side effects of alemtuzumab are rash, headache, pyrexia, nasopharyngitis, nausea, urinary tract infection, fatigue, insomnia, upper respiratory tract infection, herpes viral infection, urticaria, pruritus, thyroid gland disorders, fungal infection, arthralgia, pain in extremity, back pain, diarrhea, sinusitis, oropharyngeal pain, paresthesia, dizziness, abdominal pain, flushing, and vomiting (Genzyme, 2014). Other serious side effects associated with alemtuzumab include autoimmune thyroid disease, autoimmune cytopenias, infections and pneumonitis.

Serious and life-threatening autoimmune conditions such as immune thrombocytopenia (ITP) and anti-glomerular basement membrane disease can occur in patients receiving alemtuzumab (Genzyme, 2014). The FDA-approved labeling recommends complete blood counts with differential, serum creatinine levels, and urinalysis with urine cell counts at periodic intervals in patients who receive alemtuzumab, and for 48 months after the last dose of alemtuzumab.

The labeling states that alemtuzumab is associated with serious and life-threatening infusion reactions. The labeling states that alemtuzumab can only be administered in certified healthcare settings that have on-site access to equipment and personnel trained to manage anaphylaxis and serious infusion reactions. Monitor patients for two hours after each infusion. Make patients aware that serious infusion reactions can also occur after the 2-hour monitoring period.

Alemtuzumab is associated with increased risk of malignancies, including thyroid cancer, melanoma, and lymphoproliferative dosorders. Perform baseline and yearly skin examinations.

The Risk Evaluation Mitigation Strategy (REMS) Program is in place due to the black box warnings, and requires registration from prescribers, dispensing pharmacies, patients and healthcare facilities that will be administering Lemtrada.

Premedication with corticosteroids is recommended immediately prior to Lemtrada infusion and for the first 3 days of each treatment course.

Concomitant antiviral prophylaxis for herpetic viral infections is recommended, starting on the first day of each treatment course and continuing for a minimum of two months following treatment with Lemtrada or until the CD4+ lymphocyte count is greater than or equal to 200 cells per microliter, whichever occurs later.

The following laboratory tests are to be conducted at baseline and at periodic intervals for 48 months following the last treatment course of Lemtrada:

Complete blood count (CPC) with differential prior to treatment initiation and at monthly intervals thereafter.
Serum creatinine levels prior to treatment initiation and at monthly intervals thereafter.
Urinalysis with urine cell counts prior to treatment initiation and at monthly intervals thereafter.
Thyroid function tests such as TSH prior to treatment initiation and every 3 months thereafter.

Lemtrada is pregnancy category C.

Lemtrada should not be used in persons infected with HIV virus, or used concomitantly with antineoplastic or immunosuppressive therapies.

Dimethyl Fumarate

Dimethyl fumarate is an immunomodulator. The exact mechanism of action in multiple sclerosis is unknown. It is proposed that dimethyl fumarate and its metabolite, monomethyl fumarate, activates the Nuclear factor (erythroid‐derived 2) like 2 (Nrf2) pathway, which activates the antioxidant response and inhibits the inflammatory response. Dimethyl fumarate may also play a role in cytoprotection by decreasing demyelination and maintaining integrity of the blood brain barrier.

Tecfidera (dimethyl fumarate) is indicated for the treatment of patients with relapsing forms of multiple sclerosis. Tecfidera (dimethyl fumarate) has not been proven for treatment of first clinical episode (i.e. lack of formal diagnosis of relapsing form of MS). The updated Food and Drug Administration (FDA) approved prescribing labeling for Tecfidera states that it is indicated for the treatment of clinically isolated syndrome and for the treatment of relapsing forms of multiple sclerosis (MS) in adults. The labeling states relapsing forms of MS includes relapsing-remitting disease, and active secondary progressive disease (Tecfidera Prescribing Information, 2019)

Dimethyl fumarate is available as Tecfidera in 120mg and 240mg delayed‐release capsules. Tecfidera has a starting dose of 120mg orally twice daily for 7 days followed by Tecfidera 240 mg orally twice daily with or without food.

Tecfidera can cause anaphylaxis and angioedema after the first dose or at any time during treatment. Signs and symptoms have included difficulty breathing, urticaria, and swelling of the throat and tongue. Patients should be instructed to discontinue Tecfidera and seek immediate medical care should they experience signs and symptoms of anaphylaxis or angioedema.

A fatal case of progressive multifocal leukoencephalopathy (PML) occurred in a patient with MS who received Tecfidera for 4 years while enrolled in a clinical trial. PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. During the clinical trial, the patient experienced prolonged lymphopenia (lymphocyte counts predominantly <0.5x109/L for 3.5 years) while taking Tecfidera. The role of lymphopenia in this case is unknown. The patient had no other identified systemic medical conditions resulting in compromised immune system function and had not previously been treated with natalizumab, which has a known association with PML. The patient was also not taking any immunosuppressive or immunomodulatory medications concomitantly. At the first sign or symptom suggestive of PML, withhold Tecfidera and perform an appropriate diagnostic evaluation. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.

Tecfidera may decrease lymphocyte counts resulting in lymphopenia. In the MS placebo controlled trials, mean lymphocyte counts decreased by approximately 30% during the first year of treatment with Tecfidera and then remained stable. Four weeks after stopping Tecfidera, mean lymphocyte counts increased but did not return to baseline. The incidence of infections and serious infections was similar in patients treated with Tecfidera or placebo, respectively. A CBC is recommended before initiating treatment as well as annually. Withholding treatment should be considered in patients with serious infections until the infection is resolved.

Tecfidera may cause flushing (e.g. warmth, redness, itching, and/or burning sensation). In clinical trials, 40% of Tecfidera treated patients experienced flushing. Flushing symptoms began soon after initiation of therapy and typically improved or resolved over time. Majority of flushing symptoms were mild or moderate in severity with only 3% of patients discontinued Tecfidera for flushing. Administration of Tecfidera with food may reduce the incidence of flushing.

Fetal Risk: Pregnancy category C. May cause fetal harm. Pregnancy registry available for patients.

Fingolimod

On September 22, 2010, the FDA approved fingolimod (Gilenya capsules; formerly spelled Gilenia), the first oral drug for MS. Fingolimod is indicated for reduction of relapses and delay of disability progression in patients with relapsing forms of MS. Fingolimod is a sphingosine-1-phosphate-receptor (S1PR) modulator. Activated S1PRs help regulate the movement of lymphocytes throughout the body. Phosphorolated fingolimod antagonizes S1PR. When fingolimod inhibits these receptors, therer are decreased levels of lymphocytes in the blood due to the sequestering of lymphocytes in the lymph nodes and the prevention of the release of lymphocytes from the thymos. Although the mechanism of action in multiple sclerosis is unknown, it is thought that through this inhibition, the lymphocytes are unable to destroy the myelin sheath which leads to the lesions that are characteristic of multiple sclerosis. Gilenya (fingolimod) is indicated for the treatment of patients with relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability, Fingolimod is available as Gilenya in 0.5 mg capsules. Gilenya 0.5 mg is taken orally once daily, with or without food.

Fingolimod is contraindicated in the following

Recent (within the last 6 months) occurrence of: myocardial infarction, unstable angina, stroke, transient ischemic attack, decompesated heart failure requiring hospitalization, or ClassIII/IV heart failure.
History or presence of Mobitz Type II 2nd degree or 3rd degree ACV block or sick sinus syndrome, unless the patient has a pacemaker.
Baseline QTc interval greater than or equal to 500 ms
Treatment with Class Ia or Class III anti-arrhythmic drugs.

Fingolimod is associated with the following drug interactions

Class 1a (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic drugs: fingolamod associated with bradycardia and antiarrhymic drugs may increase the risk of Torsades in these patients.
Vaccines, immunosuppressive, immunomodulating, antineoplastic therapyies may result in increased risk of infection.

Warnings and precautions

Bradyarrhythmia and atrioventricular blocks: Fingolimod decreases heart rate and requires monitoring of patients upon first dose for six hours. Antiarrthythmics and beta blockers can increase risk of related complications. Further considerations for first dose monitoring include:
- Observe all patients for signs and symptoms of bradycardia for at least six hours after first does with hourly pulse and blood pressure measurement. Obtain ECG prior to dosing and at the end of the observation period.
- Patients who develop a heart rate less than 45 bpm, or a new onset of 2nd degree or higher atrioventricular block should be monitored until resolution of the finding. Patints at lowest post-dose heart rate at the end of the observation period should be monitored until heart rate increases.
- In patinets experiencing symptomatic bradycardia, begin continuous ECG monitoring until the symptoms have resolved; if pharmacological intervention is required to treat bradycardia, continuous ECG monitoring should continue overnight in a medical facility, and first-dose monitoring procedures should be repeated for the second dose.
- Patients at higher risk of symptomatic bradycardia or heart block because of a coexisting medical condition or certain concomitant medications should be observed overnight with contiuous ECG monitoring.
- Patients with prolonged QTc interval at baseline or during the observation period, or taking drugs with known risk of Torsades des pointes should be observed overnight with continous ECG monitoring.

Infections

Fingolimod decreases periopheral lymphocyte count due to lymphocytes sequestration in lymphoid tissue. Immunosuppressants, antineoplastics, immunomodulators, and vaccines increase risk of infection.

Macular edema

Rare in clinical studies but significant in that it may be confused with optic neuritis. Ophthalmology evaluation is recommended prior to therapy and thereafter.

Fetal risk

Pregnancy category C. May cause fetal harm. Contraception during treatment and up to 2 months after discontinuation. Pregnancy registry for patients and providers.

PML

A case of progressive multifocal leukoencephalopathy (PML) and a case of probably PML occured in patients with MS who received fingolimod in post-marketing setting. At the first sign or symptom syggestive of PML, discontinue Gilenya (fingolimod) and perform an appropriate diagnostic evaluation.

Nolan et al (2013) examined if fingolimod, an oral sphingosine-1-phosphate receptor modulator approved for treatment of MS, generally leads to increased retinal tissue volume. In this longitudinal observational study, these researchers compared changes in macular volume on spectral-domain OCT between consecutive patients with MS who initiated fingolimod and a matched reference cohort of patients with MS never exposed to the drug. The primary reference cohort was matched based on time interval between OCT examinations. A secondary reference cohort was matched based on age and disease duration. Change in macular volume within each group was analyzed using the paired-t test. Change in macular volume between groups was examined using multiple linear regressions. Macular volume increased by a mean of 0.025 mm3 (95 % confidence interval [CI]: +0.017 to +0.033, p < 0.001) in the 30 patients with MS who initiated fingolimod over a mean follow-up time of 5 months (SD 3). Macular volume did not significantly change over a mean follow-up time of 6 months (SD 4) in a comparison group of 30 patients with MS never treated with fingolimod (mean change of -0.003 mm3, 95 % CI: -0.009 to +0.004, p = 0.47). Overall, 74 % of eyes in the fingolimod-treated group exhibited an increase in macular volume versus 37 % of eyes in the comparison group. The authors concluded that initiation of fingolimod in MS is associated with a modest, relatively rapid increase in macular volume.

Zarbin et al (2013) reported outcomes of ophthalmic evaluations in clinical studies of patients receiving fingolimod for MS. Analysis done on pooled safety data (n = 2,615, all studies group) from 3 double-masked, randomized, parallel-group clinical trials (phase 2 core and extension greater than 5 years, and phase 3 FREEDOMS and TRANSFORMS core and extension studies). Patients aged 18 to 55 years (18 to 60 years in phase 2 study) diagnosed with relapsing-remitting MS were included. Patients with diabetes mellitus or ME at screening were excluded. Participants received fingolimod (0.5/1.25 mg), placebo, or interferon beta for the respective study durations. Ophthalmic examination included detailed eye history (at screening), visual acuity (VA) assessment, dilated ophthalmoscopy, OCT, and fluorescein angiography (FA). Extensive ophthalmic monitoring was performed for all patients. While being studied, patients with abnormal findings on dilated ophthalmoscopy and OCT compatible with ME were further studied by FA. All locally diagnosed ME cases were centrally reviewed by the retina specialist (M.A.Z.) on the Data and Safety Monitoring Board. Among 2,615 patients assessed, 19 confirmed ME cases were observed in fingolimod-treated groups (0.5 mg: n = 4, 0.3 %; 1.25 mg: n = 15, 1.2 %). Most patients (n = 13, 68 %) presented with blurred vision, decreased VA, or eye pain. Macular edema was diagnosed within 3 to 4 months of treatment initiation in most cases (n = 13, 68 %); 2 patients had late onset (greater than 12 months) ME. Of the 19 patients with ME, 5 (26 %), all treated with fingolimod 1.25 mg, had a history of uveitis compared with 26 (1 %) in the all studies group. In most cases (n = 16, 84 %), ME resolved after discontinuing the study drug; 11 patients required topical anti-inflammatory medications. No patient had further vision deterioration. The authors concluded that fingolimod 0.5 mg is associated with a low incidence of ME in MS studies. Patients with a history of uveitis may be at an increased risk of developing ME. An ophthalmic examination before initiating fingolimod therapy and regular follow-up eye examinations during fingolimod therapy are recommended.

A review on “Macular edema associated with fingolimod“ (Jain and Bhatti, 2012) published in EyeNet (by the American Academy of Ophthalmology) stated that “The initial evaluation of patients taking fingolimod should include a complete ophthalmic examination, including dilated fundus examination. A macular contact lens may assist in the assessment of macular thickening. The use of OCT as a screening tool is not mandatory. In our practice, we are more likely to obtain a baseline OCT in patients with uveitis, diabetic retinopathy, recent intraocular surgery or optic nerve pallor. Also, we perform Amsler grid testing and teach patients how to perform the test at home. We occasionally will perform FA, particularly in patients with diabetic retinopathy and possible macular edema. Repeat ophthalmic examination should be performed at three to four months, as most cases of FAME [fingolimod-associated macular edema] develop within this time period. Patients with visual symptoms, abnormal Amsler grid testing, decreased best-corrected visual acuity or macular thickening on clinical examination should undergo OCT and/or FA. We perform follow-up surveillance at six months and annually thereafter. We advise our patients to return sooner if they experience any visual symptoms”.

Glatiramer Acetate

Copaxone (glatiramer acetate) is indicated for the treatment of relapsing forms of multiple sclerosis. Glatiramer acetate consists of the acetate salts of synthetic polypeptides, containing four naturally occurring amino acids: L‐glutamic acid, L‐alanine, L‐tyrosine, and L‐lysine. The mechanism(s) by which glatiramer acetate exerts its effects in multiple sclerosis patients is not fully elucidated. It is thought to act by modifying immune processes that are currently believed to be responsible for pathogenesis of multiple sclerosis (MS).

Glatiramer acetate injection (Copaxone, Teva Pharmaceutical Industries Ltd., Jerusalem, Israel) has been approved by the U.S. Food and Drug Administration (FDA) for the reduction of the frequency of relapses in relapsing remitting MS, including patients who have experienced a first clinical episode and have MRI features consistent with MS. The FDA approved an expanded indication for glatiramer acetate injection to include the treatment of patients who have experienced a first clinical episode and have MRI features consistent with MS. Copaxone (glatiramer acetate for subcutaneous injection) is available as single‐use prefilled syringes containing 20 mg or 40mg of glatiramer acetate for daily or three‐times per‐week administration, respectively. The recommended dose of Copaxone (glatiramer acetate) is 20 mg injected subcutaneously once daily or 40 mg injected three times per week. The updated Food and Drug Administration (FDA) approved prescribing labeling for Copaxone states that it is indicated for the treatment of clinically isolated syndrome and for the treatment of relapsing forms of multiple sclerosis (MS) in adults. The labeling states relapsing forms of MS includes relapsing-remitting disease, and active secondary progressive disease (Copaxone Prescribing Information, 2019)

Up to 85 % of MS patients initially experience a single neurological event suggestive of MS, known as clinically isolated syndrome (CIS), and it has been demonstrated that early treatment initiation delays conversion from CIS to clinically definite MS (CDMS). The FDA granted approval of Copaxone after reviewing the results of the PreCISe study, which indicated time to development of a second exacerbation was significantly delayed in patients treated with glatiramer acetate injection compared to placebo (hazard ratio = 0.55; 95 % CI: 0.40 to 0.77; p = 0.0005). The cumulative probability of developing the second attack during the 3-year study period was significantly lower in the glatiramer acetate injection group versus the placebo group (24.7 % versus 42.9 %). The PreCISe study was a multinational, multi-center, prospective, double-blind, randomized, Phase III study that included 481 patients presenting with a single clinical episode and MRI scans suggestive of MS. Patients included were those who had a unifocal disease manifestation (i.e., clinical evidence of a single lesion). Patients received either glatiramer acetate 20mg/day or placebo as a subcutaneous injection and continued treatment for up to 3 years, unless a second exacerbation was experienced. Patients who experienced a second exacerbation continued the trial on active treatment for an additional 2 years. The primary efficacy outcome was time to development of second exacerbation. A pre-planned interim analysis was performed on data accumulated from 81 % of the 3-year placebo-controlled study exposure. The investigators reported that the 25th percentile of number of days to second exacerbation with glatiramer acetate injection increased from 336 days to 722 days compared with placebo (hazard ratio = 0.55; 95 % CI: 0.40 to 0.77). In addition, the investigators reported that there was a significant reduction in the number of new T2 lesions and in the number of T1-enhancing lesions in the glatiramer acetate injection arm compared to the placebo arm, both at year-1 and year-2 MRI scans.

Copaxone Injection is considered contraindicated in patients with hypersensitivity to glatiramer acetate or mannitol.

The only recommended route of administration of glatiramer acetate is by subcutaneous administration.

In a clinical study, Copaxone 40mg was demonstrated to be statistically superior to placebo in reducing the number of relapses over 12 months when given three times per week. Superiority to once daily glatiramer administration or any other disease modifying treatment for MS has not been demonstrated.

In April 2015, Glatopa (glatiramer acetate, Momenta Pharmaceuticals and Sandoz) became the first FDA-approved generic version of Copaxone. Like Copaxone, Glatopa is indicated to treat individuals with relapsing forms of multiple sclerosis. Glatopa consist of the acetate salts of synthetic polypeptides, containing four naturally occurring amino acids: L‐glutamic acid, L‐alanine, L‐tyrosine, and L‐lysine. The mechanism(s) by which glatiramer acetate exerts its effects in multiple sclerosis patients is not fully elucidated. It is thought to act by modifying immune processes that are currently believed to be responsible for pathogenesis of multiple sclerosis (MS). Glatiramer acetate is indicated for the treatment of relapsing forms of multiple sclerosis. Glatiramer acetate for subcutaneous injection is available as Copaxone in single‐use prefilled syringes containing 20 mg or 40mg of glatiramer acetate for daily or three‐times per‐week administration, respectively and Glatopa in single‐use pre‐filled syringes containing 20mg of glatiramer acetate for daily administration. The recommended dose of Glatopa (glatiramer acetate injection) is 20 mg injected subcutaneously once daily.

Teriflunomide

Teriflunomide is a pyrimidine synthesis inhibitor. Teriflunomide reversibly inhibits dihydroorotate dehydrogenase, a mitochondrial enzyme involved in pyrimidine synthesis. The exact mechanism by which teriflunomide exerts its therapeutic effects in MS is unknown but may involve a reduction in the number of activated lymphocytes in the CNS.

Aubagio (teriflunomide) is indicated for the treatment of patients with relapsing forms of multiple sclerosis.

Teriflunomide is available as Aubagio in 7mg and 14mg tablets. Aubagio 7mg and 14mg is taken orally once daily, with or without food.

Teriflunomide is contraindicated in patients with severe hepatic impairment. Various calculator tools are available to determine severity of hepatic impairment. The Child‐Pugh score is one measure of hepatic impairment severity. The components of this score are: hepatic encephalopathy, ascites, INR, serum albumin and total bilirubin.

Teriflunomide is contraindicated in patients who are pregnant or women of childbearing potential not using reliable contraception

Concurrent treatment with leflunomide and teriflunomide is contraindicated.

Elimination of Aubagio can be accelerated by administration of cholestyramine or activated charcoal for 11 days.

Aubagio may decrease WBC. A recent CBC should be available before starting.

Aubagio. Monitor for signs and symptoms of infection. Consider suspending treatment in case of serious infection. Do not start therapy in patient with an active infection.

If patient develops symptoms consistent with peripheral neuropathy, evaluate patient and consider discontinuing.

Stop Aubagio if patient develops Stevens‐Johnson syndrome or toxic epidermal necrolysis.

Aubagio may increase blood pressure. Measure blood pressure at treatment initiation and monitor during treatment

Monitoring of teriflunomide includes:

ALT levels within 6 months before initiation of therapy and at least monthly for 6 months after initiation.
CBC within 6 months before initiation and as necessary.
Prior to initiation, screen patients for latent tuberculosis infection.
Renal function if warranted.
Potassium levels if warranted.
Blood pressure before initiation and periodically during treatment

Dalfampridine

Ampyra (dalfampridine) is a 4‐aminopyridine that selectively blocks fast‐acting axonal potassium channels. When blocked, potassium is kept in the demyelinated axon which prolongs nerve action, not allowing it to dissipate, which in turn increases synaptic conduction and restores minimal neurologic function. Ampyra (dalfampridine) is the first orally administered medication filed for the treatment of underlying neurological deficits in patients with multiple sclerosis (MS). Studies suggest patients taking dalfampridine may experience an increase in ambulation and a decrease in self‐reported disability. Ampyra (dalfampridine) is indicated to improve walking in patients with multiple sclerosis. Ampyra (dalfampridine) is available as 10mg tablets. The recommended dose of Ampyra (dalfampridine) is one tablet taken twice daily.

Dalfampridine is the first agent to shown to improve the resultant motor function disability from MS and is used as an add‐on therapy to other immunomodulators.

The filed indication is to improve walking in patients with Multiple Sclerosis. The most common adverse effects consistent in all three trials were urinary tract infection, insomnia, dizziness, headache, asthenia, and back pain. These adverse events were described as mild‐to‐moderate, and appeared to be more severe as the doses were increased. A more serious adverse event to note occurred in two patients in the MS‐F202 trial and one patient in each of the other two phase III trials was seizures. In MS‐F202, both patients were critically ill and taking higher doses of the medications. Specialists note that seizures are commonly associated with multiple sclerosis and one of the seizures occurred in the placebo arm.

A REMS program is in place for dalfampridine and will consist of a communication strategy to pharmacists and providers regarding the risk of seizures and dalfampridine’ use in renally impaired patients. Acorda will submit REMS assessments to the FDA at 18 months, 3, years, and 7 years from the date of approval.

Ampyra (dalfampridine) will be distributed through a specialty pharmacy network.

Dalfampridine is available as Ampyra in 10 mg extended release tablets. The maximum recommended dose of Ampyra is 10 mg twice a day (approximately 12 hours apart), with or without food.

Ampyra (dalfampridine) is not recommended for patients with the following concomitant conditions: known hypersensitivity to or any of its components; pregnancy; nursing mothers; and pediatric Use.

Ampyra (dalfampridine) should be avoided in persons with a history of seizure disorder, and in moderate to severe renal impairment (CrCl<50ml/min).

Daclizumab

In 2009, the manufacturer voluntarily removed daclizumab (Zenapax) from the market (MPR, 2009). In March 2018, daclizumab (Zinbryta) was withdrawn from the market worldwide due to safety concerns (MSAA, 2018).

Biomarker of Responsiveness to Natalizumab

Mattoscio and colleagues (2015) determined the mobilization from the bone marrow and the functional relevance of the increased number of circulating hematopoietic stem and progenitor cells (HSPC) induced by the anti-α-4 integrin antibody natalizumab in patients with MS. These researchers evaluated CD45(low)CD34+ HSPC frequency by flow cytometry in blood from 45 natalizumab-treated patients (12 of whom were prospectively followed during the 1st year of treatment as part of a pilot cohort and 16 prospectively followed for validation), 10 untreated patients with MS, and 24 healthy donors. In the natalizumab-treated group, these investigators also assessed sorted HSPC cell cycle status, T- and B-lymphocyte subpopulation frequencies (n = 29), and HSPC differentiation potential (n = 10). Natalizumab-induced circulating HSPC were predominantly quiescent, suggesting recent mobilization from the bone marrow, and were capable of differentiating ex-vivo. Circulating HSPC numbers were significantly increased during natalizumab, but heterogeneously, allowing the stratification of mobilizer and non-mobilizer subgroups. Non-mobilizer status was associated with persistence of disease activity during treatment. The frequency of B cells and CD103+CD8+ regulatory T cells persistently increased, more significantly in mobilizer patients, who also showed a specific naive/memory B-cell profile. The authors concluded that the findings of this study suggested that natalizumab-induced circulating HSPC increase is the result of true mobilization from the bone marrow and has clinical and immunologic relevance. They stated that HSPC mobilization, associated with clinical remission and increased proportion of circulating B and regulatory T cells, may contribute to the treatment's mode of action; thus, HSPC blood counts could represent an early biomarker of responsiveness to natalizumab.

Biomarker of Responsiveness to Interferon-Beta

Lopez-Gomez et al (2016) evaluated the effects of interferon-beta (IFNβ) treatment on the expression of the splice variants of the Tumor necrosis factor-Related Apoptosis Inducing Ligand (TRAIL) and its receptors in different cell subpopulations (CD14+, CD4+ and CD8+) from patients with MS, and examined if this expression discriminated responders from non-responders to IFNβ therapy. These researchers examined mRNA expression of the TRAIL and TRAIL receptors variants in patients with MS, at baseline and after 1 year of IFNβ therapy, according to responsiveness to this drug. Long-term therapy with IFNβ increased the expression of TRAIL-α in T cell subsets exclusively from responders and decreased the expression of the isoform 2 of TRAILR-2 in monocytes from responders as well as non-responders. Lower expression of TRAIL-alpha, and higher expression of TRAIL-beta in monocytes and T cells, was found before the onset of IFNβ therapy in patients who will subsequently become responders. Baseline expression of TRAILR-1 was also significantly higher in monocytes and CD4+ T cells from responders. The authors concluded that the findings of the present study showed that long-term IFNβ treatment had a direct influence on TRAIL-alpha and TRAILR-2 isoform 2 expression. Besides, receiver operating characteristic analysis revealed that the baseline expression of TRAIL-alpha in monocytes and T cells, and that of TRAILR-1 in monocytes and CD4+ T cells, showed a predictive value of the clinical response to IFNβ therapy, pointing to a role of TRAIL system in the mechanism of action of IFNβ in MS that will need further investigation.

Novel Agents (e.g., Ocrelizumab, and Ofatumumab)

In a review on new drug therapies for MS, Mangas et al (2010) reviewed the most recent data on drug candidates for MS. In the pre-clinical phase, such drug candidates have shown a beneficial effect on the onset of experimental autoimmune encephalomyelitis (microtubule-stabilizing drugs, MS14, lithium, GEMSP...), a decrease in CNS cell infiltrates (recombinant T cell receptor ligand, lovastatin-rolipram, ribavirin, GEMSP...), prevention of demyelination (lovastatin-rolipram, calpain inhibitor, lithium...); and a reduction of axonal loss (phenytoin, lovastatin-rolipram, calpain inhibitor).

Gensicke et al (2012) stated that natalizumab was the first monoclonal antibody to be approved for the treatment of MS. Several other monoclonal antibodies are in development and have demonstrated promising efficacy in phase II studies. They can be categorized according to their mode of action into compounds targeting

leukocyte migration into the CNS (natalizumab);
cytolytic antibodies (rituximab, ocrelizumab, ofatumumab, alemtuzumab); or
antibodies and recombinant proteins targeting cytokines and chemokines and their receptors (daclizumab, ustekinumab, atacicept, tabalumab [Ly-2127399], secukinumab [AIN457]).

In a randomized, double-blind, placebo-controlled, phase II clinical trial, Sorensen and colleagues (2014) examined the safety and effectiveness of the human CD20 monoclonal antibody ofatumumab in RRMS. Patients received 2 ofatumumab infusions (100 mg, 300 mg, or 700 mg) or placebo 2 weeks apart. At week 24, patients received alternate treatment; safety and effectiveness were assessed. A total of 38 patients were randomized (ofatumumab/placebo, n = 26; placebo/ofatumumab, n = 12) and analyzed; 36 completed the study. Two patients in the 300-mg group withdrew from the study because of AEs. No unexpected safety signals emerged. Infusion-related reactions were common on the first infusion day but not observed on the second infusion day. None of the patients developed human anti-human antibodies. Ofatumumab was associated with profound selective reduction of B cells as measured by CD19(+) expression. New brain MRI lesion activity was suppressed (greater than 99 %) in the first 24 weeks after ofatumumab administration (all doses), with statistically significant reductions (p < 0.001) favoring ofatumumab found in new T1 gadolinium-enhancing lesions, total enhancing T1 lesions, and new and/or enlarging T2 lesions. The authors concluded that ofatumumab (up to 700 mg) given 2 weeks apart was not associated with any unexpected safety concerns and was well-tolerated in patients with RRMS; MRI data suggested a clinically meaningful effect of ofatumumab for all doses studied. They stated that these findings warrant further exploration of ofatumumab in RRMS.

Straus Farber et al (2016) noted that since 2004, 5 drugs with new mechanisms of action have been approved by the FDA for the treatment of relapsing forms of MS. The expanded armamentarium of treatment options offers new opportunities for improved disease control and increased tolerability of medications, and also presents new safety concerns and monitoring requirements with which physicians must familiarize themselves. These investigators reviewed each of the newly approved agents – alemtuzumab, dimethyl fumarate, fingolimod, natalizumab, and teriflunomide -- with regard to their mechanism of action, clinical trial data, safety and tolerability concerns, and monitoring requirements. They also reviewed available data for promising agents that are currently in late-phase clinical trials, including daclizumab, ocrelizumab, and ofatumumab.

Shirani et al (2016) reviewed various therapies currently undergoing phase II or III clinical trials, including antioxidants (idebenone); tyrosine kinase inhibitors (masitinib); sphingosine receptor modulators (siponimod); monoclonal antibodies (anti-leucine-rich repeat and immunoglobulin-like domain containing neurite outgrowth inhibitor receptor-interacting protein-1, ocrelizumab, intrathecal rituximab); hematopoietic stem cell therapy; statins and other possible neuroprotective agents (amiloride, riluzole, fluoxetine, oxcarbazepine); lithium; phosphodiesterase inhibitors (ibudilast); hormone-based therapies (adrenocorticotrophic hormone and erythropoietin); T-cell receptor peptide vaccine (NeuroVax); autologous T-cell immunotherapy (Tcelna); MIS416 (a microparticulate immune response modifier); dopamine antagonists (domperidone); and nutritional supplements, including lipoic acid, biotin, and sunphenon epigallocatechin-3-gallate (green tea extract). The authors stated that given ongoing and planned clinical trial initiatives, and the largest ever focus of the global research community on progressive MS, future prospects for developing targeted therapeutics aimed at reducing disability in progressive forms of MS appear promising.

Gasperi e al (2016) stated that several therapeutic agents have been approved for the treatment of RRMS, aiming at the reduction of relapses and a delay in disability progression. The authors noted that 3 therapeutic monoclonal antibodies targeting CD20-positive B cells (ocrelizumab, ofatumumab, and rituximab) were investigated in MRI-based phase II and phase III clinical trials in RRMS, providing consistent evidence for a disease-ameliorating effect of B cell depleting therapies in MS.

Estrogen Receptor Beta Ligands

Itoh and colleagues (2017) stated that protective effects of pregnancy during MS have led to clinical trials of estriol, the pregnancy estrogen, in MS. Since estriol binds to estrogen receptor (ER) beta, ER beta ligand could represent a "next generation estriol" treatment since ER beta ligand treatment was protective in experimental autoimmune encephalomyelitis (EAE) in both sexes and across genetic backgrounds. Neuroprotection was shown in spinal cord, sparing myelin and axons, and in brain, sparing neurons and synapses. Longitudinal in-vivo MRIs showed decreased brain atrophy in cerebral cortex gray matter and cerebellum during EAE. The authors concluded that investigation of ER beta ligand as a neuro-protective treatment for MS is warranted.

Interleukin-10 / Interleukin-16

Kinzel and Weber (2016) stated that over the past 10 years, evidence condensed that B cells, B cell-derived plasma cells and antibodies play an important role in the pathogenesis and progression of MS. In many patients with MS, peripheral B cells show signs of chronic activation; within the CSF clonally expanded plasma cells produce oligoclonal immunoglobulins, which remain a hallmark diagnostic finding. Confirming the clinical relevance of these immunological alterations, recent trials testing anti-CD20-mediated depletion of peripheral B cells showed an instantaneous halt in development of new CNS lesions and occurrence of relapses. Notwithstanding this enormous success, not all B cells or B cell subsets may contribute in a pathogenic manner, and may, in contrast, exert anti-inflammatory and, thus, therapeutically desirable properties in MS. Naive B cells, in MS patients similar to healthy controls, are a relevant source of regulatory cytokines such as interleukin-10, which dampens the activity of other immune cells and promotes recovery from acute disease flares in experimental MS models. These investigators described in detail pathogenic but also regulatory properties of B and plasma cells in the context of MS and its animal model experimental autoimmune encephalomyelitis. In addition, these researchers reviewed what impact current and future therapies may have on these B cell properties; and focused on the highly encouraging data on anti-CD20 antibodies as future therapy for MS. The author also discussed how B cell-directed therapy in MS could be possibly advanced even further in regard to safety and effectiveness by integrating the emerging information on B cell regulation in MS into future therapeutic strategies.

Skundric (2018) re-evaluated fundamental approaches of current MS therapies with focus being placed on their targeted underlying immune, molecular and cellular mechanisms. Currently used therapies were discussed in regard to their mechanisms of action, clinical accomplishments and unwanted AEs and complications. Special emphasis was given to current disease modifying therapies (DMT) and their actions at immune mechanisms of disease. Effects on DMT on CD4+Th1 cells and related cytokine and signaling pathways were discussed in more detail. Attention was paid to emerging role of a cytokine IL-16 in regulation of relapsing MS and its model, EAE. Immune mechanisms mediated by IL-16 were critically evaluated in the context of mechanisms of DMT and its potential as prospective MS therapy.

Mesenchymal Stem Cell Therapy

In a systematic review, Oliveira and colleagues (2019) examined the safety, tolerability, and efficacy of mesenchymal stem cells (MSCs) therapies in the treatment of patients with MS; 3 electronic databases (Web of Science, PubMed, and Cochrane) were searched from April until June 2019. Clinical trials or case reports with information related to the effects of MSC therapies in MS patients were considered for this review. A total of 10 manuscripts were selected, namely 7 uncontrolled clinical trials, 2 RCTs, and 1 case report. The overall quality of the studies was considered good. Besides minor AEs, there were 1 case of encephalopathy with seizures and 2 cases of iatrogenic meningitis, which were not related to the treatment, but with the administration route. The analyses of the EDSS in the uncontrolled clinical trials showed that 48 patients improved, 39 maintained and 16 worsened their clinical condition. Regarding the randomized studies, 1 did not show statistically significant variations in the mean EDSS score and in the other the mean EDSS score was statistically significantly lower for the experimental group. The case report also showed an improvement in the EDSS score. The authors concluded that MSCs transplantation proved to be a safe and tolerable therapy. Their potential therapeutic benefits were also validated. Moreover, these researchers stated that larger placebo-controlled, blinded clinical trials are needed to determine the long-term safety and efficacy profile of these therapies for MS.

Mesenchymal Stromal Cell-Derived Neural Progenitors

Harris et al (2016) previously characterized the immuno-regulatory and trophic properties of neural progenitors derived from bone marrow mesenchymal stromal cells (MSC-NPs) and established that cells derived from MS and non-MS patients alike were therapeutically viable. In an experimental model of MS, intrathecal MSC-NP injection resulted in disease amelioration with decreased T-cell infiltration, and less severe lesion pathology associated with recruitment of resident progenitors to inflammatory sites. In a pilot feasibility study, these researchers examined safety and dosing of intrathecal MSC-NP therapy in 6 patients with MS. Patients with progressive MS and advanced disability who were refractory to all other conventional MS treatments were enrolled in the study. For each dose, MSC-NP cells were cultured from autologous MSCs and tested for quality control before intrathecal administration. Patients were evaluated for AEs and neurological status to assess safety of the treatment. Six patients with progressive MS were treated with between 2 and 5 intrathecal injections of escalating doses of autologous MSC-NPs and were followed-up for an average of 7.4 years after initial injection. There were no safety concerns noted, no serious AEs, and the multiple dosing regimen was well-tolerated; 4 of the 6 patients showed a measurable clinical improvement following MSC-NP treatment. The authors concluded that the findings of this pilot study supported preliminary first-in-human safety and tolerability of autologous MSC-NP treatment for MS. These preliminary findings need to be validated by well-designed studies.

Myelin Basic Protein Peptides

Lomakin et al (2016) previously showed that immunodominant myelin basic protein (MBP) peptides encapsulated in mannosylated liposomes (Xemys) effectively suppressed EAE. Within the frames of the successfully completed phase I clinical trial, these researchers investigated changes in the serum cytokine profile after Xemys administration in MS patients. These investigators observed a statistically significant decrease of MCP-1/CCL2, MIP-1β/CCL4, IL-7, and IL-2 at the time of study completion. In contrast, the serum levels of TNF-α were remarkably elevated. The authors concluded that these data suggested that the administration of Xemys led to a normalization of cytokine status in MS patients to values commonly reported for healthy subjects; these data are an important contribution for the upcoming Xemys clinical trials.

Belogurov et al (2016) previously showed that CD206-targeted liposomal delivery of co-encapsulated immunodominant MBP sequences MBP46-62, MBP124-139 and MBP147-170 (Xemys) suppressed EAE in dark Agouti rats. These researcher evaluated the safety of Xemys in the treatment of patients with RRMS and SPMS, who failed to achieve a sustained response to first-line disease-modifying therapies. In a phase I, open-label, dose-escalating, proof-of-concept study, a total 20 patients with RRMS or SPMS received weekly subcutaneously injections with ascending doses of Xemys up to a total dose of 2.675 mg. Clinical examinations, including EDSS score, MRI results, and serum cytokine concentrations, were assessed before the first injection and for up to 17 weeks after the final injection; Xemys was safe and well-tolerated when administered for 6 weeks to a maximum single dose of 900 μg; EDSS scores and numbers of T2-weighted and new gadolinium-enhancing lesions on MRI were statistically unchanged at study exit compared with baseline; nonetheless, the increase of number of active gadolinium-enhancing lesions on weeks 7 and 10 in comparison with baseline was statistically significant. During treatment, the serum concentrations of the cytokines monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, and IL-7 decreased, whereas the level of TNF-α increased. The authors concluded that these results provided evidence for the further development of Xemys as an antigen-specific, disease-modifying therapy for patients with MS.

Serum Neurofilament as a Marker of Neuroaxonal Injury in Early MS and for Monitoring Disease Activity

Kuhle and colleagues (2017) examined a potential effect of riluzole on serum neurofilaments (Nf) compared to placebo and the relationship between longitudinal clinical and MRI outcomes and serum Nf levels. Serum samples were obtained from participants enrolled in a randomized double-blind trial of neuroprotection with riluzole versus placebo as an add-on to weekly interferon-β (IFN-β)-1a IM initiated 3 months after randomization; Nf measurements were performed by ELISA and electrochemiluminescence immunoassay. Longitudinal serum samples were available from 22 riluzole and 20 placebo participants over 24 months. There was no observed treatment effect with riluzole; Nf light chain (NfL) levels decreased over time (p = 0.007 at 24 months), whereas the Nf heavy chain was unchanged (p = 0.997). Changes in NfL were correlated with EDSS change (p = 0.009) and neuropsychological outcomes. Brain volume decreased more rapidly in patients with high baseline NfL (p = 0.05 at 12 months and p = 0.008 at 24 months) and this relationship became stronger at 24 months (p = 0.024 for interaction). Higher and increasing NfL predicted higher number of gadolinium-enhancing lesions (p < 0.001 for both). The authors concluded that these findings supported the potential value of serum NfL as a marker of neuroaxonal injury in early MS. Its reduction over time could represent regression to the mean, or a possible treatment effect of IFN-β-1a. The association with whole brain atrophy and the formation of acute white matter lesions has relevant implications to use serum NfL as a non-invasive biomarker of the overall consequences of brain damage and ongoing disease activity. Moreover, they stated that these findings should be interpreted with caution and need to be replicated independently including a broader range of patients with cognitive changes. The unexpected lack of association of NfH with clinical and most imaging outcomes needs to be investigated further to determine whether the difference relates to disease stage. The drawbacks of this study included the relatively small sample size limiting the ability to detect a treatment effect of riluzole on various markers. Due to the design of the original trial, longitudinal samples from untreated patients or healthy controls were not available. Finally, analyses of Nf were not a priori defined in the original trial, hence not corrected for multiple comparisons and therefore exploratory in nature.

In an editorial that accompanied the afore-mentioned study, Bodini and Calabresi (2017) stated that prospective longitudinal studies including patients with all phenotypes of the disease and healthy controls, directly comparing Nf with MR-derived metrics over time, will be able to establish whether Nf, alone or combined with other imaging biomarkers, can have a place in MS clinical practice and therapeutic trials. Such studies could also inform on the evolution of Nf levels over a long time course, determining the rate and the timeframe in which Nf levels rise and fall in each individual. They also noted that another major issue that needs to be addressed is reproducibility, which remains suboptimal. This was particularly true for Nf quantified on serum samples, which even more than CSF samples are affected by the lack of reproducibility validation. These editorialists concluded that presently the measure of CNS and serum Nf levels is an interesting candidate to quantify neuroaxonal degeneration in MS, but remains for now a research tool. They stated that further validation steps are needed before considering Nf biomarkers of neuroaxonal degeneration a reliable outcome measure for clinical trials of neuroprotective treatments.

Novakova and colleagues (2017) examined the effects of disease activity, disability, and disease-modifying therapies (DMTs) on serum neurofilament light (NFL) and the correlation between NFL concentrations in serum and CSF in MS. NFL concentrations were measured in paired serum and CSF samples (n = 521) from 373 participants: 286 had MS, 45 had other neurologic conditions, and 42 were healthy controls (HCs). In 138 patients with MS, the serum and CSF samples were obtained before and after DMT treatment with a median interval of 12 months. The CSF NFL concentration was measured with the UmanDiagnostics NF-light enzyme-linked immunosorbent assay (ELISA). The serum NFL concentration was measured with an in-house ultrasensitive single-molecule array assay. In MS, the correlation between serum and CSF NFL was r = 0.62 (p < 0.001). Serum concentrations were significantly higher in patients with RRMS (16.9 ng/L) and in patients with progressive MS (23 ng/L) than in HCs (10.5 ng/L, p < 0.001 and p < 0.001, respectively). Treatment with DMT reduced median serum NFL levels from 18.6 (interquartile range [IQR] 12.6 to 32.7) ng/L to 15.7 (IQR 9.6 to 22.7) ng/L (p < 0.001). Patients with relapse or with radiologic activity had significantly higher serum NFL levels than those in remission (p < 0.001) or those without new lesions on MRI (p < 0.001). These investigators noted that the high correlation between serum and CSF NFL suggested that the temporal course of serum NFL was similar to that described for CSF NFL. However, this has to be further investigated in prospective studies. In monitoring of the effect of DMT on axonal damage, a 3-month interval between blood tests for monitoring serum NFL would reveal the occurrence of new disease activity. However, these researchers could not determine from their data whether this would detect a step-wise accumulation of T2 lesions, accumulation of disability, or conversion to a progressive disease course. There is a need for long-term follow-up studies to collect data on the correlation between NFL concentrations over time and such outcomes. The authors concluded that these findings suggested that measuring serum NFL may be useful in trials and in clinical practice for evaluating the effect of DMTs in MS.

Osteopontin as a Biomarker for MS

Agah and colleagues (2018) conducted a systematic review and meta-analysis of studies that measured peripheral blood and CSF levels of osteopontin (OPN) in MS patients and controls to evaluate the diagnostic potential of this biomarker. These investigators searched PubMed, Web of Science and Scopus databases to find articles that measured OPN concentration in peripheral blood and CSF samples from MS patients up to October 19, 2016. Q statistic tests and the I2 index were applied for heterogeneity assessment. If the I2 index was less than 40 %, the fixed-effects model was used for meta-analysis. Random-effects meta-analysis was chosen if the I2 value was greater than 40 %. After removal of duplicates, a total of 918 articles were identified, and 27 of them fulfilled the inclusion criteria. These researchers included 22 eligible studies in the final meta-analysis; MS patients, in general, had considerably higher levels of OPN in their CSF and blood when compared to all types of controls (p < 0.05). When the comparisons were made between different subtypes of MS patients and controls, the results pointed to significantly higher levels of OPN in CSF of MS subgroups (p < 0.05). All subtypes of MS patients, except clinically isolated syndrome (CIS); patients, had increased blood levels of OPN compared to controls (p < 0.05). In the second set of meta-analyses, these researchers compared the peripheral blood and CSF concentrations of OPN between MS patient subtypes; CIS patients had significantly lower levels of OPN both in their peripheral blood and CSF compared to patients with progressive subtypes of MS (p < 0.05); CSF concentration of OPN was significantly higher among RRMS patients compared to the CIS patients and SPMS patients (p < 0.05). Finally, patients with active MS had significantly higher OPN levels in their CSF compared to patients with stable disease (p = 0.007). The authors stated that although the existing data strongly suggested that higher levels of OPN were present in peripheral blood and CSF of MS patients compared to the controls, very limited studies were included in most of the subgroup analyses; so to achieve more reliable results, more studies needed to be included in these subgroups. They also stated that considerable heterogeneity among the included studies was another drawback of this study. Furthermore, publication bias was a challenging issue in biomarker studies which may affect results of meta-analyses and their reliability. The authors concluded that the result of this study confirmed that increased levels of OPN exist in CSF and peripheral blood of MS patients and strengthened the evidence regarding the clinical utility of OPN as a promising and validated biomarker for MS. An elevated level of OPN in a patient at risk of MS may be suggestive of active inflammation. They stated that given the fact that OPN levels were higher during relapses, monitoring this biomarker might be able to predict the disease course.

Clemastine Fumarate for the Treatment of Chronic Demyelinating Injury in MS

In a randomized, controlled, double-blind, single-center, cross-over study, Green and colleagues (2017) examined the safety and efficacy of clemastine fumarate as a treatment for patients with MS. Patients with relapsing MS with chronic demyelinating optic neuropathy on stable immunomodulatory therapy were eligible for this study. Patients who fulfilled international panel criteria for diagnosis with disease duration of less than 15 years were eligible. Patients were randomly assigned (1:1) via block randomization using a random number generator to receive either clemastine fumarate (5.36 mg orally twice-daily) for 90 days followed by placebo for 60 days (group 1), or placebo for 90 days followed by clemastine fumarate (5.36 mg orally twice-daily) for 60 days (group 2). The primary outcome was shortening of P100 latency delay on full-field, pattern-reversal, visual-evoked potentials. These researchers analyzed by intention-to-treat. Between January 1, 2014 and April 11, 2015, these researchers randomly assigned 50 patients to group 1 (n = 25) or group 2 (n = 25); all patients completed the study. The primary efficacy end-point was met with clemastine fumarate treatment, which reduced the latency delay by 1.7 ms/eye (95 % CI: 0.5 to 2.9; p = 0.0048) when analyzing the trial as a cross-over. Clemastine fumarate treatment was associated with fatigue, but no serious AEs were reported. The authors concluded that this was the first RCT to document efficacy of a re-myelinating drug for the treatment of chronic demyelinating injury in MS. They stated that these findings suggested that myelin repair can be achieved even following prolonged damage.

Ocrelizumab (Ocrevus) for the Treatment of Secondary Progressive MS

An UpToDate review on “Treatment of progressive multiple sclerosis in adults” (Olek, 2018) does not mention ocrelizumab as a therapeutic option for secondary progressive MS.

Respiratory Rehabilitation / Respiratory Muscle Training in MS

An American Academy of Neurology systematic evidence review of rehabilitation in multiple sclerosis (Haselkorn et al, 2015) concluded that a 10-week inspiratory muscle training program possibly is effective for improving maximal inspiratory pressure as measured by pulmonary function testing in relapsing-remitting MS (RRMS), secondary progressive multiple sclerosis (SPMS), and primary progressive multiple sclerosis (PPMS), Expanded Disability Status Scale (EDSS) 2–6.5 (1 study, Class II objective measures). The evidence review found that data are inadequate to support/refute the use of inspiratory muscle training for fatigue and expiratory muscle training.

Rietberg and colleagues (2017) examined the effects of respiratory muscle training versus any other type of training or no training for respiratory muscle function, pulmonary function and clinical outcomes in people with MS. These investigators searched the Trials Register of the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group (February 3, 2017), which contained trials from the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, CINAHL, LILACS and the trial registry databases ClinicalTrials.gov and World Health Organization (WHO) International Clinical Trials Registry Platform. Two authors independently screened records yielded by the search, hand-searched reference lists of review articles and primary studies, checked trial registers for protocols, and contacted experts in the field to identify further published or unpublished trials. These researchers included RCTs that investigated the efficacy of respiratory muscle training versus any control in people with MS. One reviewer extracted study characteristics and study data from included RCTs, and 2 other reviewers independently cross-checked all extracted data. Two review authors independently assessed risk of bias with the Cochrane “risk of bias” assessment tool. When at least 2 RCTs provided data for the same type of outcome, these researchers performed meta-analyses. They assessed the certainty of the evidence according to the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach. A total of 6 RCTs, comprising 195 participants with MS were included in this analysis. Two RCTs investigated inspiratory muscle training with a threshold device; 3 RCTs, expiratory muscle training with a threshold device; and 1 RCT, regular breathing exercises; 18 participants (˜approximately 10 %) dropped out; trials reported no serious AEs. These investigators pooled and analyzed data of 5 trials (n = 137) for both inspiratory and expiratory muscle training, using a fixed-effect model for all but one outcome. Compared to no active control, meta-analysis showed that inspiratory muscle training resulted in no significant difference in maximal inspiratory pressure (mean difference (MD) 6.50 cm H2O, 95 % CI: -7.39 to 20.38, p = 0.36, I2 = 0 %) or maximal expiratory pressure (MD -8.22 cmH2O, 95 % CI: -26.20 to 9.77, p = 0.37, I2 = 0 %), but there was a significant benefit on the predicted maximal inspiratory pressure (MD 20.92 cm H2O, 95 % CI: 6.03 to 35.81, p = 0.006, I2 = 18 %). Meta-analysis with a random-effects model failed to show a significant difference in predicted maximal expiratory pressure (MD 5.86 cm H2O, 95 % CI: -10.63 to 22.35, p = 0.49, I2 = 55 %). These studies did not report outcomes for health-related quality of life (QOL); 3 RCTS compared expiratory muscle training versus no active control or sham training. Under a fixed-effect model, meta-analysis failed to show a significant difference between groups with regard to maximal expiratory pressure (MD 8.33 cm H2O, 95 % CI: -0.93 to 17.59, p = 0.18, I2 = 42 %) or maximal inspiratory pressure (MD 3.54 cm H2O, 95 % CI: -5.04 to 12.12, p = 0.42, I2 = 41 %). One trial assessed QOL, finding no differences between groups. For all pre-determined secondary outcomes, such as forced expiratory volume, forced vital capacity and peak flow pooling was not possible. However, 2 trials on inspiratory muscle training assessed fatigue using the Fatigue Severity Scale (range of scores 0 to 56 ), finding no difference between groups (MD, -0.28 points, 95 % CI:-0.95 to 0.39, p = 0.42, I2 = 0 %). Due to the low number of studies included, these researchers could not perform cumulative meta-analysis or subgroup analyses. It was not possible to perform a meta-analysis for AEs, no serious AEs were mentioned in any of the included trials. The quality of evidence was low for all outcomes because of limitations in design and implementation as well as imprecision of results. The authors concluded that this review provided low-quality evidence that resistive inspiratory muscle training with a resistive threshold device was moderately effective post-intervention for improving predicted maximal inspiratory pressure in people with mild-to-moderate MS, whereas expiratory muscle training showed no significant effects. The sustainability of the favorable effect of inspiratory muscle training is unclear, as is the impact of the observed effects on QOL.

Levy and associates (2018) performed a systematic review of the published literature related to respiratory rehabilitation in MS. These investigators searched the databases Medline via PubMed, PEDro and Cochrane Library for English or French reports of clinical trials and well-designed cohorts published up to December 2016 with no restriction on start date by using the search terms "multiple sclerosis", "respiratory rehabilitation", "respiratory muscle training", "lung volume recruitment", "cough assistance", and "mechanical in-exsufflation". Literature reviews, case reports and physiological studies were excluded. The Maastricht criteria were used to assess the quality of clinical trials. These researchers followed the Oxford Centre for Evidence-Based Medicine guidelines to determine level of evidence and grade of recommendations. Among the 21 reports of studies initially selected, 11 were retained for review; 7 studies were RCTs, 2 were non-RCTs, and 2 were observational studies. Respiratory muscle training (inspiratory and/or expiratory) by use of a portable resistive mouthpiece was the most frequently evaluated technique, with 2 level-1 RCTs. Another level-1 RCT evaluated deep-breathing exercises. All reviewed studies evaluated home-based rehabilitation programs and focused on spirometric outcomes. The disparities in outcome measures among published studies did not allow for a meta-analysis and cough assistance devices were not evaluated in this population. The authors concluded that although respiratory muscle training can improve maximal respiratory pressure in MS and lung volume recruitment can slow the decline in vital capacity, evidence is lacking to recommend specific respiratory rehabilitation programs adapted to the level of disability induced by the disease.

Intravesical Vanilloids for the Treatment of Neurogenic Lower Urinary Tract Dysfunction in Multiple Sclerosis

On behalf of the Neuro-Urology Promotion Committee of the ICS, Phe and associates (2018) evaluated available evidence on the safety and efficacy of vanilloids for the treatment of neurogenic lower urinary tract dysfunction (NLUTD) in patients with MS. This systematic review and meta-analysis was performed according to the PRISMA statement. Studies were identified by electronic search of Cochrane register, Embase, Medline, Scopus, (last search January 8, 2016). After screening a total of 7,848 abstracts, 4 RCTs and 3 prospective cohort studies were included. Pooled data from 3 RCTs evaluating intravesical capsaicin showed the standardized mean difference (SMD) to be -2.16 (95 % CI: -2.87 to -1.45) in incontinence episodes/24 hours and -0.54 (95 % CI: -1.03 to -0.05) in voids/24 hours. There was no statistically significant effect on maximum cystometric capacity and maximum storage detrusor pressure. Overall, AEs were reported by greater than 50 % of the patients, most commonly were pelvic pain, facial flush, worsening of incontinence, autonomic dysreflexia, urinary tract infection and hematuria. Risk of bias and confounding was relevant in both RCTs and non-RCTs. The authors concluded that preliminary data suggested that intravesical vanilloids might be effective for treating NLUTD in patients with MS. However, the safety profile appeared unfavorable, the overall quality of evidence was low and no licensed substance is currently available. These researchers stated that well-designed, adequately sampled and properly powered RCTs are needed to further investigate the safety and effectiveness of intravesical vanilloids for the treatment of NLUTD in patients with MS.

Medicinal Cannabinoids for the Treatment of Pain, Spasticity and Bladder Dysfunction in Multiple Sclerosis

Torres-Moreno and colleagues (2018) noted that cannabinoids have anti-spastic and analgesic effects; however, their role in the treatment of MS symptoms is not well-defined. These investigators carried out a systematic review and meta-analysis to examine the efficacy and tolerability of medicinal cannabinoids compared with placebo in the symptomatic treatment of patients with MS. Data sources included Medline and the Cochrane Library Plus up to July 26, 2016; no restrictions were applied. The search was completed with information from ClinicalTrials.gov. Randomized, double-blind, and placebo-controlled trials evaluating the effect of medicinal cannabinoids by oral or oro-mucosal route of administration on the symptoms of pain, spasticity, or bladder dysfunction in adult patients with MS were selected for analysis. The PRISMA reporting guidelines were followed. Effect sizes were calculated as SMD for efficacy, and rate ratio for tolerability. Within each study, those SMDs evaluating the same outcome were combined before the meta-analysis to obtain a single value per outcome and study. Pooling of the studies was performed on an intention-to-treat (ITT) basis by means of random-effect meta-analysis. Main outcome measures were pain, spasticity (on the Ashworth and Modified Ashworth scales and subjective), bladder dysfunction, AEs and withdrawals due to AEs. A total of 17 selected trials including 3,161 patients were analyzed. Significant findings for the efficacy of cannabinoids versus placebo were SMD = -0.17 SD (95 % CI: -0.31 to -0.03 SD) for pain, -0.25 SD (95 % CI: -0.38 to -0.13 SD) for spasticity (subjective patient assessment data), and -0.11 SD (95 % CI: -0.22 to -0.0008 SD) for bladder dysfunction. Results favored cannabinoids. Findings for tolerability were rate ratio = 1.72 patient-years (95 % CI: 1.46 to 2.02 patient-years) in the total AEs analysis and 2.95 patient-years (95 % CI: 2.14 to 4.07 patient-years) in withdrawals due to AEs. Results described a higher risk for cannabinoids. The serious AEs meta-analysis showed no statistical significance. The authors concluded that the findings of this study suggested that cannabinoids produced a limited and mild reduction of pain, subjective spasticity, and bladder dysfunction in patients with MS, but no changes in objectively measured spasticity. They can be considered safe drugs, as the analysis of serious AEs did not show statistical significance, although the total number of AEs was higher than in placebo for the treatment of symptoms in patients with MS. Moreover, these researchers stated that shortcomings exist with respect to research into the efficacy of cannabinoids in the treatment of MS; the quantity of available studies is limited. There is no evidence of studies that examine the efficacy of cannabinoids versus other treatments in MS. They noted that research into the possible combinations of cannabinoids and other therapies might result in greater synergy benefits than in an individual form.

The authors stated that the drawbacks of this study entailed the small number of studies included; differences in the length of treatment, particularly in tolerability calculations; inclusion of cross-over studies as parallel design; calculations made on the basis of an ITT principle by data extrapolation, which may have provoked bias in the findings, although ITT analysis is the standard for medication evaluation; and publication bias. Another potential drawback was that blinding procedures could be affected in studies with drugs with such large difficulties in masking and blinding. Consequently, a large allocation-dependent placebo effect could be expected. This was particularly evident in the study with 2 phases in which the responders in the 1st phase were selected for the 2nd phase. In addition, most of the studies included were funded by the pharmaceutical industry, especially for nabiximols. As explained in the “Results” section, the exclusion of these studies had an impact on the results on subjective spasticity. In the interpretation of trends favoring experimental or control treatments, difficult decisions arose in some cases owing to the different forms of exposure across the studies.

Non-Pharmacological Interventions for the Treatment of Chronic Pain in Multiple Sclerosis

Amatya and colleagues (2018) stated that chronic pain is common and significantly impacts on the lives of persons with MS (pwMS). Various types of non-pharmacological interventions are widely used, both in hospital and ambulatory/mobility settings to improve pain control in pwMS, but the safety and effectiveness of many non-pharmacological modalities is still unknown. In a Cochrane review, these investigators examined the safety and effectiveness of non-pharmacological therapies for the management of chronic pain in pwMS. Specific questions to be addressed by this review include the following: Are non-pharmacological interventions (uni-disciplinary and/or multi-disciplinary rehabilitation) effective in reducing chronic pain in pwMS? What type of non-pharmacological interventions (uni-disciplinary and/or multi-disciplinary rehabilitation) are effective (least and most effective) and in what setting, in reducing chronic pain in pwMS? A literature search was performed using the specialized register of the Cochrane MS and Rare Diseases of the Central Nervous System Review Group, using the Cochrane MS Group Trials Register which contains CENTRAL, Medline, Embase, CINAHL, LILACUS, Clinical trials.gov and the WHO International Clinical Trials Registry Platform on December 10, 2017. Hand-searching of relevant journals and screening of reference lists of relevant studies was carried out. All published RCTs and cross-over studies that compared non-pharmacological therapies with a control intervention for managing chronic pain in pwMS were included. Clinical controlled trials (CCTs) were eligible for inclusion. All 3 review authors independently selected studies, extracted data and assessed the methodological quality of the studies using the GRADE tool for best-evidence synthesis. Pooling data for meta-analysis was not possible due to methodological, clinical and statistically heterogeneity of the included studies. A total of 10 RCTs with 565 subjects that examined different non-pharmacological interventions for the management of chronic pain in MS fulfilled the review inclusion criteria. The non-pharmacological interventions evaluated included: transcutaneous electrical nerve stimulation (TENS), psychotherapy (telephone self-management, hypnosis and electroencephalogram (EEG) biofeedback), transcranial random noise stimulation (tRNS), transcranial direct stimulation (tDCS), hydrotherapy (Ai Chi) and reflexology. There was very low-level evidence for the use of non-pharmacological interventions for chronic pain such as TENS, Ai Chi, tDCS, tRNS, telephone-delivered self-management program, EEG biofeedback and reflexology in pain intensity in pwMS. Although there were improved changes in pain scores and secondary outcomes (such as fatigue, psychological symptoms, spasm in some interventions), these were limited by methodological biases within the studies. The authors concluded that despite the use of a wide range of non-pharmacological interventions for the treatment of chronic pain in pwMS, the evidence for these interventions is still limited or insufficient, or both. These researchers stated that more studies with robust methodology and greater numbers of participants are needed to justify the use of these interventions for the management of chronic pain in pwMS.

Functional Electrical Stimulation (FES) Cycling

In a systematic review, Scally and associates (2019) examined the outcomes of pwMS with mobility impairment following functional electrical stimulation (FES) cycling intervention. These researchers carried out a systematic search of 4 electronic databases (Medline, Web of Science, CINAHL and PEDro) from their inception to January 8, 2019. Inclusion criteria were: human participants with definite diagnosis of MS, age of 18 years, and participants with mobility impairment (determined as an average participant EDSS of greater than or equal to 6.0). Initial searches found 1,163 studies. 9 of which met the full inclusion criteria: 5 pre-post studies with no control group, 2 RCTs, 1 retrospective study, and 1 case study; 2 studies had the same participant group and intervention but reported different outcomes. Outcome data were available for n = 76 unique participants, with n = 82 completing a FES cycling intervention. Of the n = 4 papers with clear drop-out rates, pooled drop-out rate was 25.81 %; 2 papers reported non-significant improvements in aerobic capacity following a FES cycling intervention. A total of 4 papers reported no change in lower limb strength and 2 papers reported significant reductions in spasticity post-training; 4 studies failed to provide information regarding AEs with the other studies reporting n = 10 AEs across 36 participants. The authors concluded that the findings of this study suggested that FES cycle training may reduce cardiovascular disease risk alongside trends for a reduction in spasticity post-training, however the low quality of the literature precluded any definitive conclusions.

Pilutti and Motl (2019) provided a summary of the current evidence for FES cycling as an exercise training modality in pwMS with respect to prescription, safety, tolerability, and acute and chronic effects. These investigators searched the literature for studies involving FES cycling exercise in persons with MS published in English up until July 2019. A total of 8 studies were retrieved: 2 studies examined acute effects, 2 studies examined chronic effects, and 4 studies reported on both acute and chronic effects of FES cycling exercise. The overall quality of the studies was low, with only 1, small, RCT. There is limited but promising evidence for the application of FES cycling exercise among persons with MS who have moderate-to-severe disability. Participants were capable of engaging in regular FES cycling exercise (approximately 30 mins, 2 to 3 times/week), with few, mild AEs experienced. The authors concluded that preliminary evidence from small, mostly uncontrolled trials supported the potential benefits of FES cycling on physiological fitness, walking mobility, and symptoms of fatigue and pain. Moreover, these researchers stated that high-quality RCTs of FES cycling exercise are needed for providing recommendations for integrating exercise training in the management of advanced MS.

In an assessor-blinded, pilot RCT, Pilutti and colleagues (2019) examined the efficacy of supervised FES cycling exercise in pwMS on secondary outcomes, including cognition, fatigue, pain, and health-related QOL. A total of 11 adult participants with MS were randomized to receive FES cycling exercise (n = 6) or passive leg cycling (n = 5) for 24 weeks. Cognitive processing speed was assessed using the Symbol Digit Modalities Test. Symptoms of fatigue and pain were assessed using the Fatigue Severity Scale, the Modified Fatigue Impact Scale, and the short-form McGill Pain Questionnaire. Physical and psychological health-related QOL were assessed using the 29-item MSIS. A total of 8 participants (4, FES; 4, passive leg cycling) completed the intervention and outcome assessments. The FES cycling exercise resulted in moderate-to-large improvements in cognitive processing speed (d = 0.53), fatigue severity (d = -0.92), fatigue impact (d = -0.45 to -0.68), and pain symptoms (d = -0.67). The effect of the intervention on cognitive performance resulted in a clinically meaningful change, based on established criteria. The authors concluded that FES cycling exercise might have beneficial effects on cognition and symptoms of fatigue and pain. Moreover, these researchers stated that larger RCTs are needed to confirm these preliminary findings and establish the potential of this rehabilitation approach for PwMS with higher disability levels. They noted that considering the limited evidence for exercise interventions overall, and FES cycling specifically, in PwMS with higher disability levels, the findings of this pilot study were novel and promising.

The authors stated that the findings of this study were limited by its small sample size (n = 5 for FES cycling) and the EDSS score range of the participants included in this trial, which may limit the generalizability of the findings. The outcomes reported were not the primary outcomes of the trial, and thus, subjects were not selected for inclusion based on criteria related to these measures; however, scores on some of the outcomes reflected an elevated symptomology based on criterion values (e.g., FSS score greater than or equal to 4.0 indicates severe fatigue). These investigators noted that participatory outcomes in this trial were limited to health-related QOL measures. They stated that future studies should examine other participatory measures, such as employment, recreation and leisure, and activities of daily living (ADL). The intervention was delivered in a supervised laboratory environment, and it was unclear whether similar results would be obtained in other clinical, community, or home-based settings. It will be important to examine the feasibility and efficacy of FES cycling for PwMS in other environments to determine the potential of FES cycling exercise as an advanced rehabilitation approach. They further highlighted the importance of examining the timeline of adaptations and the potential for lasting effects of FES cycling exercise, especially in this population.

Appendix

List: 2010 Revised McDonald Criteria for Diagnosis of MS in Disease with Progression from Onset

PPMS may be diagnosed in subjects with:

One year of disease progression (retrospectively or prospectively determined)
Plus 2 of the 3 following criteria†:

Evidence for dissemination in space (DIS) in the brain based on > 1 T2‡ lesions in at least 1 area characteristic for MS (periventricular, juxtacortical, or infratentorial);
Evidence for DIS in the spinal cord based upon > 2 T2‡ lesions in the cord;
Positive CSF (isoelectric focusing evidence of oligoclonal IgG bands and/or increased IgG index).

† If the subject has a brainstem or spinal cord syndrome, all symptomatic lesions are excluded from the criteria.

‡ Gadolinium enhancement of lesions is not required.

Source: Polman, et al., 2011 (available at: Table 4: The 2010 McDonald Criteria for Diagnosis of MS).

Specific Phobia: DSM 5 Diagnostic Criteria

A market fear or anxiety about a specific object or situation (e.g., flying, heights, animals, receiving an injection, seeing blood). Note: In children, the fear or anxiety may be expressed by crying, tantrums, freezing, or clinging.
The phobic object or situation almost always provokes immediate fear or anxiety.
The phobic object or situation is actively avoided or endured with intense fear or anxiety.
The fear or anxiety is out of proportion to the actual danger posed by the specific object or situation and to the sociocultural context.
The fear, anxiety, or avoidance is persistent, typically lasting for 6 months or more.
The fear, anxiety, or avoidance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.
The disturbance is not better explained by the symptoms of another mental disorder, including fear, anxiety, and avoidance of situations associated with panic-like symptoms or other incapacitating symptoms (as in agoraphobia); objects or situations related to obsessions (as in obsessive-compulsive disorder); reminders of traumatic events (as in posttraumatic stress disorder); separation from home or attachment figures (as in separation anxiety disorder); or social situations (as in social anxiety disorder).

Source: APA, 2013.

Expanded Disability Status Scale (EDSS)

The EDSS scale ranges from 0 to 10 in 0.5 unit increments that represent higher levels of disability. Scoring is based on an examination by a neurologist.

Table: Expanded Disability Status Scale (EDSS)
EDSS Scale Range	Disability Status
1.0	No disability, minimal signs in one FS
1.5	No disability, minimal signs in more than one FS
2.0	Minimal disability in one FS
2.5	Mild disability in one FS or minimal disability in two FS
3.0	Moderate disability in one FS, or mild disability in three or four FS. No impairment to walking
3.5	Moderate disability in one FS and more than minimal disability in several others. No impairment to walking
4.0	Significant disability but self-sufficient and up and about some 12 hours a day. Able to walk without aid or rest for 500m
4.5	Significant disability but up and about much of the day, able to work a full day, may otherwise have some limitation of full activity or require minimal assistance. Able to walk without aid or rest for 300m
5.0	Disability severe enough to impair full daily activities and ability to work a full day without special provisions. Able to walk without aid or rest for 200m
5.5	Disability severe enough to preclude full daily activities. Able to walk without aid or rest for 100m
6.0	Requires a walking aid - cane, crutch, etc - to walk about 100m with or without resting
6.5	Requires two walking aids - pair of canes, crutches, etc - to walk about 20m without resting
7.0	Unable to walk beyond approximately 5m even with aid. Essentially restricted to wheelchair; though wheels self in standard wheelchair and transfers alone. Up and about in wheelchair some 12 hours a day
7.5	Unable to take more than a few steps. Restricted to wheelchair and may need aid in transfering. Can wheel self but can not carry on in standard wheelchair for a full day and may require a motorised wheelchair
8.0	Essentially restricted to bed or chair or pushed in wheelchair. May be out of bed itself much of the day. Retains many self-care functions. Generally has effective use of arms
8.5	Essentially restricted to bed much of day. Has some effective use of arms retains some self care functions
9.0	Confined to bed. Can still communicate and eat
9.5	Confined to bed and totally dependent. Unable to communicate effectively or eat/swallow
10.0	Death due to MS

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code	Code Description
*Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+"*:
CPT codes covered when selection criteria are met:
36514	Therapeutic apheresis; for plasma pheresis [not covered for chronic or secondary progressive MS (maintenance therapy)]
CPT codes not covered for indications listed in the CPB:
Interleukin-1 gene polymorphisms testing - no specific codes:
35476	Transluminal balloon angioplasty, percutaneous; venous
36522	Photopheresis, extracorporeal
38204	Management of recipient hematopoietic progenitor cell donor search and cell acquisition
38205	Blood-derived hematopoietic progenitor cell harvesting for transplantation per collection; allogenic
38206	autologous
38207	Transplant preparation of hematopoietic progenitor cells; cryopreservation and storage
38208	thawing of previously frozen harvest, without washing
38209	thawing of previously frozen harvest, with washing
38210	specific cell depletion within harvest, T-cell depletion
38211	tumor cell depletion
38212	red blood cell removal
38213	platelet depletion
38214	plasma (volume) depletion
38215	cell concentration in plasma, mononuclear, or buffy coat layer
38230	Bone marrow harvesting for transplantation
38240	Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor
82728	Ferritin
83520	Immunoassay, analyte quantitative; not otherwise specified [if reported for neutralizing antibodies against interferon beta]
83540	Iron
83873	Myelin basic protein, cerebrospinal fluid
84146	Prolactin
86367	Stem cells (ie, CD34), total count [not covered for measurements of hematopoietic stem and progenitor cells counts as a biomarker of responsiveness to natalizumab]
86376	Microsomal antibodies (eg, thyroid or liver-kidney), each
86382	Neutralization test, viral [if reported for neutralizing antibodies against interferon beta]
87253	Virus isolation; tissue culture, additional studies or definitive identification (eg, hemabsorption, neutralization, immunofluorescence stain), each isolate [if reported for neutralizing antibodies against interferon beta]
88360	Morphometric analysis, tumor immunohistochemistry (eg, Her-2/neu, estrogen receptor/progesterone receptor), quantitative or semiquantitative, per specimen, each single antibody stain procedure; manual [estrogen receptor beta ligands]
88361	Morphometric analysis, tumor immunohistochemistry (eg, Her-2/neu, estrogen receptor/progesterone receptor), quantitative or semiquantitative, per specimen, each single antibody stain procedure; using computer-assisted technology [estrogen receptor beta ligands]
90283	Immune globulin (IgIV), human, for intravenous use
90880	Hypnotherapy
90901	Biofeedback training by any modality
90911	Biofeedback training, perineal muscles, anorectal or urethral sphincter, including EMG and/or manometry
92540	Basic vestibular evaluation, includes spontaneous nystagmus test with eccentric gaze fixation nystagmus, with recording, positional nystagmus test, minimum of 4 positions, with recording, optokinetic nystagmust test, bidirectional foveal and peripheral stimulation, with recording, and oscillating tracking test, with recording
92541 - 92548	Vestibular function tests, with recording (e.g., ENG, PENG), and medical diagnostic evaluation
92550	Tympanometry and reflex threshold measurements
92558	Evoked otoacoustic emissions, screening (qualitative measurement of distortion product or transient evoked otoacoustic emissions), automated analysis
92567	Tympanometry (impedance testing)
92568 - 92569	Acoustic reflex testing
92570	Acoustic immittance testing, includes tympanometry (impedance testing), acoustic reflex threshold testing, and acoustic reflex decay testing
92587 - 92588	Evoked otoacoustic emissions
93886	Transcranial Doppler study of the intracranial arteries; complete study
96912	Photochemotherapy; psoralens and ultraviolet A (PUVA)
96913	Photochemotherapy (Goeckerman and/or PUVA) for severe photoresponsive dermatoses requiring at least four to eight hours of care under direct supervision of the physician (includes application of medication and dressings)
97010	Application of a modality to 1or more areas; hot or cold packs
97036	Application of a modality to 1or more areas; Hubbard tank, each 15 minutes
97124	Therapeutic procedure, 1 or more areas, each 15 minutes; massage, including effleurage, petrissage and/or tapotement (stroking, compression, percussion)
97140	Manual therapy techniques (eg, mobilization/manipulation, manual lymphatic drainage, manual traction), 1 or more regions, each 15 minutes
99183	Physician or other qualified health care professional attendance and supervision of hyperbaric oxygen therapy, per session
Other CPT codes related to the CPB:
88271 - 88275	Molecular cytogenetics
99601 - 99602	Home infusion/specialty drug administration
96365 - 96368	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug)
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
HCPCS codes covered if selection criteria are met:
Plegridy, Aubagio, Gilenya, Tecfidera, Cladribine (Mavenclad), Siponimod (Mayzent), Ozanimod (Zeposia) - no specific code:
J0202	Injection, alemtuzumab, 1 mg [not covered for clinically isolated syndrome]
J1595	Injection, glatiramer acetate, 20 mg
J1826	Injection, interferon beta-1a, 30 mcg
J1830	Injection, interferon beta -1b, 0.25 mg (code may be used for Medicare when drug administered under direct supervision of a physician, not for use when drug is self-administered)
J2323	Injection, natalizumab, 1 mg
J2350	Injection, ocrelizumab, 1 mg
J7500	Azathioprine, oral, 50 mg
J7501	Azathioprine, parenteral, 100 mg
J9065	Injection, cladribine, per 1 mg
J9070	Cyclophosphamide, 100 mg
J9293	Injection, mitoxantrone HCI, per 5 mg
J9312	Injection, rituximab, 10 mg [last resort treatment]
Q3027	Injection, interferon beta-1a, 1 mcg for intramuscular use
Q3028	Injection, interferon beta-1a, 1 mcg for subcutaneous use
S9338	Home infusion therapy, immunotherapy, administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drug and nursing visits coded separately), per diem
S9490	Home infusion therapy, corticosteroid infusion; administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem
S9559	Home injectable therapy, interferon, including administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drug and nursing visits coded separately), per diem
HCPCS codes not covered for indications listed in the CPB:
Serum neurofilament, Osteopontin, Clemastine fumarate, Intravesical vanilloids - no specific code:
A4556	Electrodes (e.g., apnea monitor), per pair
A4557	Lead wires (e.g., apnea monitor), per pair
A4558	Conductive gel or paste, for use with electrical device (e.g., TENS, NMES), per oz.
A4595	Electrical stimulator supplies, 2 lead, per month, (e.g. TENS, NMES)
C1725	Catheter, transluminal angioplasty, nonlaser (may include guidance, infusion/perfusion capability)
C1874	Stent, coated/covered, with delivery system,
C1876	Stent, noncoated/noncovered, with delivery system,
C1885	Catheter, transluminal angioplasty, laser
C2625	Stent, noncoronary, temporary, with delivery system
E0218	Water circulating cold pad with pump
E0691 - E0694	Ultraviolet light therapy system panel, includes bulbs/lamps, timer and eye protection; treatment area 2 sq ft or less, 4 ft panel, 6 ft panel, or ultraviolet multidirectional light therapy system in 6 ft cabinet, includes bulbs/lamps, timer and eye protection
E0720	Transcutaneous electrical nerve stimulation (TENS) device, 2 lead, localized stimulation
E0730	Transcutaneous electrical nerve stimulation (TENS) device, 4 or more leads, for multiple nerve stimulation
E0761	Non-thermal pulsed high frequency radiowaves, high peak power electromagnetic energy treatment device
E0770	Functional electrical stimulator, transcutaneous stimulation of nerve and/or muscle groups, any type, complete system, not otherwise specified (such as stimulators used in patients with footdrop) [functional electrical stimulation cycling]
J1459	Injection, immune globulin (Privigen), intravenous, nonlyophilized (e.g., liquid), 500 mg
J1556	Injection, immune globulin (bivigam), 500 mg
J1557	Injection, immune globulin, (Gammaplex), intravenous, nonlyophilized (e.g., liquid), 500 mg
J1559	Injection, immune globulin (Hizentra), 100 mg
J1561	Injection, immune globulin, (Gamunex-C/Gammaked), non-lyophilized (e.g. liquid), 500 mg
J1566	Injection, immune globulin, intravenous, lyophilized (e.g. powder), not otherwise specified, 500 mg
J1568	Injection, immune globulin, (Octagam), intravenous, non-lyophilized (e.g. liquid), 500 mg
J1569	Injection, immune globulin, (Gammagard liquid), non-lyophilized (e.g. liquid), 500 mg
J1572	Injection, immune globulin, (Flebogamma/Flebogamma Dif), intravenous, nonlyophilized (e.g., liquid), 500 mg
J1599	Injection, immune globulin, intravenous, nonlyophilized (e.g., liquid), not otherwise specified, 500 mg
J2315	Injection, naltrexone, depot form, 1 mg
J7502	Cyclosporine, oral, 100 mg
J7505	Muromonab-CD3, parenteral, 5mg
J7513	Daclizumab, parenteral, 25 mg
J7515 - J7516	Cyclosporine, oral, 25 mg or parenteral, 250 mg
J8530	Cyclophosphamide, oral, 25 mg
J8610	Methotrexate, oral, 2.5 mg
J9015	Aldesleukin, per single use vial
J9212 - J9216	Injection interferon alfacon-1, recombinant, 1 mcg, interferon, alfa-2A, recombinant, 3 million units, interferon, alfa-2B, recombinant, 1 million units, interferon alfa-N3 (human leukocyte derived), 250,000 IU, or interferon gamma-1B, 3 million units
J9250 - J9260	Methotrexate sodium, 5 mg or Methotrexate sodium, 50 mg
J9302	Injection, ofatumumab, 10 mg
J9320	Injection, streptozocin, 1 g
S0090	Sildenafil citrate, 25 mg
S2150	Bone marrow or blood-derived stem cells (peripheral or umbilical), allogeneic or autologous, harvesting, transplantation, and related complications; including: pheresis and cell preparation/storage; marrow ablative therapy; drugs, supplies, hospitalization with outpatient follow-up; medical/surgical, diagnostic, emergency, and rehabilitative services; and the number of days of pre- and post-transplant care in the global definition
S3852	DNA analysis for APOE epsilon 4 allele for susceptibility to Alzheimer's disease
Other HCPCS codes related to the CPB:
J0881	Injection, darbepoetin alfa, 1 mcg (non-ESRD use)
J0885	Injection, epoetin alfa, (for non-ESRD use), 100 units
J0888	Injection, epoetin beta, 1 microgram, (for non-ESRD use)
ICD-10 codes covered if selection criteria are met:
G35	Multiple sclerosis [primary progressive or relapsing]
G37.8	Other specified demyelinating diseases of the central nervous system [clinically isolated syndrome]
K50.00 - K50.90	Crohn’s disease
ICD-10 codes not covered for indications listed in the CPB:
G89.20	Other chronic pain [chronic pain in multiple sclerosis]
N31.0 - N31.9	Neuromuscular dysfunction of bladder, not elsewhere classified [neurogenic lower urinary tract dysfunction]
Z94.84	Stem cells transplant status

The above policy is based on the following references:

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Last Review 07/09/2020

Effective: 06/18/1998

Next Review: 03/11/2021
Review History
Definitions

Multiple Sclerosis

Least Cost Medically Necessary Brands

Extavia

Clinically Isolated Syndrome (CIS) and Relapsing forms of Multiple Sclerosis (MS)

Plegridy

Clinically Isolated Syndrome (CIS) and Relapsing forms of Multiple Sclerosis (MS)

Lemtrada

Relapsing forms of Multiple Sclerosis (MS)

Policy

Intravenous Steroid Treatment

Outpatient Treatment

Experimental and Investigational Interventions

Concomitant Use

Dosing Recommendations

Gilenya (Fingolimod)

Aubagio (teriflunomide)

Ocrevus (ocrelizumab)

Lemtrada (alemtuzumab)

Background

Clinically Isolated Syndrome (CIS)

Primary‐progressive MS (PPMS)

Relapsing‐remitting MS (RRMS)

Secondary Progressive MS (SPMS)

Steroids

ACTH

Interferon Beta-1B

Interferon Beta-1A

Cyclophosphamide

Cladribine

Mitoxantrone

Statins

Spasticity Treatments

Hyperbaric Oxygen

Erythropoietin

Ankle Foot Orthosis (AFOs)

Plasma Exchange

Neutralizing Antibodies Against Interferon Beta

Natalizumab

Apolipoprotein E Polymorphisms

Transcranial Ultrasound

Chronic Cerebrospinal Venous Insufficiency Treatment / Balloon Venoplasty

Myxovirus Resistance Protein A

gMS®Pro EDSS Test

Neurofilament Heavy Chain Protein

Prolactin

Interleukin-1

MTHFR

IVIG

Rituximab

Ocrelizumab

Infusion reactions:

Infection:

Progressive Multifocal Leukoencephalopathy (PML):

Hepatitis B virus (HBV) reactivation:

Weakened immune system:

Before receiving ocrelizumab, patients should tell their healthcare provider about all of their medical conditions, including if they:

Alemtuzumab

Dimethyl Fumarate

Fingolimod

Fingolimod is contraindicated in the following:

Fingolimod is associated with the following drug interactions:

Warnings and precautions:

Infections:

Macular edema:

Fetal risk:

PML:

Glatiramer Acetate

Teriflunomide

Dalfampridine

Daclizumab

Biomarker of Responsiveness to Natalizumab

Biomarker of Responsiveness to Interferon-Beta

Novel Agents (e.g., Ocrelizumab, and Ofatumumab)

Estrogen Receptor Beta Ligands

Interleukin-10 / Interleukin-16

Mesenchymal Stem Cell Therapy

Mesenchymal Stromal Cell-Derived Neural Progenitors

Myelin Basic Protein Peptides

Serum Neurofilament as a Marker of Neuroaxonal Injury in Early MS and for Monitoring Disease Activity

Osteopontin as a Biomarker for MS

gMS^®Pro EDSS Test

Infusion reactions

Infection

Hepatitis B virus (HBV) reactivation

Weakened immune system

Before receiving ocrelizumab, patients should tell their healthcare provider about all of their medical conditions, including if they

Fingolimod is contraindicated in the following

Fingolimod is associated with the following drug interactions

Warnings and precautions

Infections

Macular edema

Fetal risk

PML