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Multiple Sclerosis Update

Multiple Sclerosis (MS) is a condition that has no cure but is manageable with prudent treatment. There are approximately 950,000 cases of MS in the United States, with an estimated 2.3 million cases worldwide. While most patients are diagnosed between the ages of 15 and 45, it also occurs in children. MS is more commonly found in women and those of northern European ancestry or Caucasian descent. MS is the most common chronic neurologic disease of young adults; nevertheless, having a first degree relative with MS only slightly increases risk of developing the condition.

The treatment of multiple sclerosis and other demyelinating disorders tends to primarily focus upon specialty pharmacy, but there may be some component of inpatient claims with severe relapse management involving plasmapheresis or prolonged inpatient stays.

Overview of the illness

MS is an immune-mediated, chronic, inflammatory, and degenerative disease. The pathological hallmark is inflammatory, demyelinating lesions (plaques), and axonal loss in the central nervous system (CNS). MS is often characterized by relapses and remissions of neurological symptoms and progression of disability over time.

In healthy patients, nerve fibers (axons) have a protective myelin coating, which enables normal conduction of electrical impulses. In a patient with MS, the immune system attacks myelin, in a process called demyelination. This process causes inflammation in the affected areas, leading exposed axons to be damaged or destroyed. In some cases, the exposed axons may be severed, leading to permanent loss of the axon. The result is permanent loss of nerve function, which can lead to permanent disability over time. Brain atrophy may occur early in the disease, with patients’ brain tissue decreasing at approximately 0.7%-2.0% per year.

Common symptoms include:

  • weakness or numbness in one or more limbs;
  • optic neuritis;
  • tremor and ataxic gait from cerebellar dysfunction;
  • double vision, dysarthria, or dizziness from brainstem dysfunction; and
  • fatigue1

There are several disease phenotypes. Relapsing forms include relapsing-remitting (RRMS) and active secondary progressive MS. RRMS is characterized by flare-ups (relapses), followed by periods of remission. About 85% of MS patients have RRMS. Some people diagnosed with RRMS will eventually transition to secondary-progressive MS.

Secondary-progressive MS (SPMS) can follow after a period of time with RRMS. With SPMS, the disease steadily progresses. Primary-progressive MS (PPMS) is characterized by consistent worsening. About 15% of MS patients have PPMS. Clinically isolated syndrome (CIS) is characterized by an episode of neurologic symptoms that may not evolve into MS2. Radiographic isolated syndrome (RIS) results from a patient receiving a brain MRI for another reason. The MRI shows MS-like lesions.

Those with an active form of the disease experience relapses, acute or sub-acute episodes of new or increasing neurologic dysfunction, followed by full or partial recovery in the absence of fever or infection. Those with a progressive form experience steadily increasing objectively documented neurologic dysfunction/disability without unequivocal recovery, although fluctuations and phases of stability may occur.

Worsening disease is defined by a documented increase in neurologic dysfunction/disability as a result of relapse or progressive disease. “Disease progression” is reserved solely for those in a progressive phase of the illness. Confirmed progression of worsening is defined by an increase of neurologic dysfunction throughout a defined time interval, such as 3, 6, or 12 months.

In approximately 50% of cases, patients with a relapsing form of MS convert to a progressive phase within ten years. Complete recovery between relapses, referred to as benign MS, is uncommon. Patients more frequently see partial recovery between relapses and experience disability progression over their lifetime.

Diagnosis is challenging due to the variety of symptoms that may present themselves. Traditionally, doctors have diagnosed MS through the demonstration of two or more neurological events that cause CNS lesions, with objective findings and dissemination in space and time.

Other assessment tools to diagnose MS include:

  • Medical history that includes symptoms referable to the CNS
  • Neurologic examination
  • MRI changes that support diagnosis, including clinical attacks/relapses/exacerbations, brain, and spinal cord imaging, detecting subclinical lesions, and identifying active inflammation with gadolinium (Gd) contrast enhancement
  • Lumbar puncture with CSF analysis
  • Laboratory studies to exclude disease mimics
  • Evoked potential testing


Presentation, progression, and treatment are varied and must be tailored to the individual patient. In general, therapies exist to slow disease progression and treat relapses, but there is no treatment to fully stop or reverse the effects of the disease. The primary concerns center around quality of life and prospects for disability. Nevertheless, many patients will not experience severe disability—15 years after the onset of MS symptoms, approximately 20% are bedridden and 20% may use a wheelchair or crutches, but 60% may retain their ability to walk and will experience limited disability3.

The primary goal is disease management, which includes:

  1. reducing relapses and preventing or slowing progression,
  2. treating relapses,
  3. assessing and managing symptoms,
  4. improving the patient’s and caretaker’s quality of life, and
  5. monitoring disease progression.

These are achieved in a number of ways.


An MS relapse is defined by an episode of focal neurological disturbance lasting more than 24 hours continuously, without an alternate explanation or infection, and with a preceding period of clinical stability lasting at least 30 days. The onset of neurological symptoms evolve over days to weeks and plateaus within 1-2 weeks. Recovery can last up to 9 months. Duration depends on severity. Some symptoms will persist and become permanent, leading to disability.

MS patients may also experience pseudo relapses, caused by environmental or systemic influences, but not resulting from a new area of CNS inflammation. They lead to temporary worsening or return of neurological symptoms. Possible influences include increased core or environment temperature, physical exertion, fatigue, infection or illness, stress or anxiety, medication or alcohol abuse, menstrual cycle, or a surgical or medical procedure.

To manage relapses, it is first necessary to determine whether it is an acute relapse, pseudo relapse, or the result of disease progression.

Corticosteroid treatment or adrenocorticotropic hormone (ACTH) are often prescribed to treat relapses. High dose steroids or oral steroid tapers are prescribed in the first instance, although there is no evidence that steroid treatment changes the long-term outcome of the disease. Adverse effects are wide-ranging; they include hyperglycemia, hypokalemia, sodium and fluid retention; hypertension; GI tolerance, dyspepsia, increased appetite; leukocytosis, thrombocytopenia; psychiatric manifestations, insomnia; cataracts, glaucoma, retinal necrosis; bone demineralization; acne, impaired wound healing, hypersensitivity reactions; and avascular necrosis of large joints.

ACTH, meanwhile, stimulates a patient’s adrenal glands to secrete endogenous steroids. ACTH has potentially fewer side effects, not least because of lower exposure to high levels of steroids for the patient. It can nevertheless lead to psychosis, depression, and hyperglycemia and is often used as a second- or third-line agent due to its high cost.

MS patients can combine these treatments with other, non-pharmacologic relapse management tools. These can include rehabilitation, physical therapy, occupational therapy, speech therapy, community-based resources, home support, and alternative equipment.

Disease modifying therapies (DMT) are also commonly used and are particularly indicated as soon as a RRMS diagnosis is made. Treating a patient early with DMTs could prevent the development of lesions, which may delay progression of disability, and preventing early relapses may delay long-term disability. In addition, disability progresses faster in patients with poor recovery from 2nd and 3rd relapses.

There are a number of approved DMT treatments as well as several new and emerging DMT being introduced:

  • Diroximel fumarate, similar to dimethyl fumarate
  • Oral S1P1 receptor blockers, similar to fingolimod
  • Anti-CD 20 blockers, similar to rituximab, ocrelizumab
  • Injectable DMT: beta interferons and glatiramer acetate.
  • Oral DMT: fingolimod, teriflunomide, dimethyl fumarate, cladribine , and siponimod
  • Infused DMT: natalizumab, alemtuzumab, ofatumumab, and ocrelizumab

Glatiramer acetate, interferons, teriflunomide and dimethyl fumarate serve as immunomodulators, which means they are medications used to help regulate or normalize the immune system. Fingolimod, ocrelizumab, natalizumab, cladribine, ofatumumab, and alemtuzumab serve as immunosuppressors, which means they subdue the immune response.

Injectable DMT

Beta Interferons:

  • Beta interferon 1-b (Betaseron®4, Extavia®5)
  • Beta interferon 1-a IM, beta interferon 1-a SC (Avonex®6, Plegridy®7, Rebif®8)

Glatiramer Acetate:

  • 20 mg/l subcutaneous injection daily (Copaxone®9, Glatect™10 and Glatopa™11)
  • 40 mg/l subcutaneous injection 3-times weekly (Copaxone®, generic)

Oral DMT

Fingolimod (Gilenya®)
Teriflunomide (Aubagio®)
Dimethyl Fumarate (Tecfidera®)
Diroximel Fumarate (Vumerity®)
Cladribine (Mavenclad®)
Siponimod (Mayzent®)

Infused DMT

Natalizumab (Tysabri®)
Alemtuzumab (Lemtrada®)
Ocrelizumab (Ocrevus®)
Ofatumumab (Kesimpta®)

Treatment costs

Some high cost therapies, such as HP Acthar® Gel at $55,000 a vial and Ampyra®12 at $50,000 per year, are focused on relapse management or function/symptom reduction and thus may be appropriately taken in addition to a disease modifying therapy.

Treatment choices continue to expand rapidly and have an array of price tags attached.

  • Oral therapies are projected between $100,000 and $140,000 yearly.
  • IV therapies are projected at $100,000 to $120,000 yearly.
  • Lemtrada® (alemtuzumab) is $400,000 for the first year and $150,000 for subsequent year(s). A total of two years treatment is standard.
  • Soliris® (eculizumab) is $40,000/1200 mg dose. It is given every two weeks at a maintenance cost of $1,000,000 per year, and was FDA approved for use only for neuromyelitis optica spectrum disorder (NMOSD). NMOSD is a rare autoimmune disease of the central nervous system that mainly affects the optic nerves and spinal cord and is on the multiple sclerosis (MS) spectrum. Injectable therapies are generally projected at $110,000 to $135,000 yearly.

One of the newest specialty pharmaceutical drugs approved by the FDA on June 11, 2020 is Uplizna™13(inebilizumab-cdon). It is an injection for intravenous use for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients with a particular antibody (patients who are anti-aquaporin-4 or AQP4 antibody positive).

Even newer than this is Kesimpta®, just approved on August 20, 202014. Kesimpta® is the only self-administered, targeted B-cell therapy for patients with multiple sclerosis. No pricing is yet available on this drug.

Treatment Summary

When deciding on a course of treatment, there are a number of considerations: efficacy – how effective the medication is at slowing down the progression of the disease; side effects; safety; monitoring; route of administration; and cost.

Generally speaking, as efficacy goes up, safety goes down and monitoring becomes more complex. Shots, such as interferons and glatiramer acetate, tend to have lower efficacy. Pills, such as teriflunomide, dimethyl fumarate, and siponimod have intermediate efficacy. Intravenous therapies including natalizumab, ocrelizumab, and alemtuzumab have the highest efficacy. Fingolimod and oral cladribine are between pills and IV therapies.

Some safety concerns are more serious than others. Immune surveillance, infections, malignancies, long-lasting and irreversible effects, autoimmunity, teratogenicity, and serious infusion reactions are among those that elicit concern. Meanwhile, bradycardia, blood pressure elevations, reactive airway disease, liver function abnormalities, flushing, GI discomfort, arthralgias, and back and limb pain are all considered manageable safety concerns.

With constantly emerging new therapies, each patient must work with their healthcare provider to evaluate the risks and benefits of each. Depending on the status of the progression of the disease, patients will choose between treatments intended to slow disease progression and/or those intended to treat relapses.

Mitigating Risk

What can be done to ensure that financial risk to our (re)insured’s is being effectively managed? PartnerRe’s PULSE + Plus® program, working with Specialty Service Providers, can offer specialty physician review services for a second opinion on diagnosis, dosage, frequency and treatment options in order to support your determinations of medical necessity.

We can also offer comprehensive high dollar claim review and negotiation, which includes a complimentary preliminary review for cases where service has already been rendered. This facilitates a determination of whether billed charges are consistent with medical billing standards and plan design, addresses charges in excess of industry-accepted reasonable and customary norms and looks at whether billing chronology mirrors the member’s clinical condition. Validation of appropriateness of diagnosis, pharmaceutical dosage and pharmaceutical cost may also be considerations.

Finally, we work to uncover therapies that are considered experimental under the plan design and identify situations where more cost effective therapies and sites of administration of high dollar specialty pharmaceuticals may be available. All of this is provided with no fee unless cost savings are realized.

Use of comprehensive, multidisciplinary Multiple Sclerosis Centers for care of members is encouraged; the Consortium of Multiple Sclerosis Centers has a directory at

Contact your PULSE + Plus® Clinical Consultant for more information on new pharmaceutical options as well as potential savings opportunities.


4 ® 2020 Bayer. All rights reserved.
5 ®Novartis Pharmaceuticals Corporation East Hanover, NJ.
6 ®2020 Biogen. All rights reserved.
7 ®2020 Biogen. All rights reserved.
8 ® 2020 EMD Serono, Inc.
9 Copaxone is a registered trademark of Teva Pharmaceutical Industries Ltd.
10 Pharmascience Inc.
11 Glatopa, GlatopaCare, and Glatopaject are registered trademarks of Novartis AG.
12 AMPYRA is marketed by Acorda Therapeutics, Inc. and manufactured under license from Alkermes Pharma Limited (APIL), Ireland.
13 TK?

Opinions expressed are those of the author. This article is for general information, education and discussion purposes only. It does not constitute legal or professional advice of PartnerRe or its affiliates.
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