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Multiple Sclerosis, Part 2: Pharmacology

Notes

Multiple Sclerosis, Part 2: Pharmacology

Sections




chronic MS pathophysiology & Pharmacotherapeutics

Here, let's turn our attention from acute to chronic MS pathophysiology and pharmacotherapeutics.

Chronic MS Pathophysiology

Chronic Inflammation & Neurodegeneration

Clinical Correlation: Multiple Sclerosis

  • Much remains unknown about why neurodegeneration occurs in MS, but over time, in many instances, patients suffer a gradual deterioration of both gray and white matter.

Brain Atrophy & MS Plaques

Let's draw an unfortunate end-outcome of unchecked MS pathology:

  • Draw a coronal section through a shrunken, atrophic brain that bears just a thin layer of gray matter and is riddled with numerous demyelinated plaques: we draw them as yellowish in color and they are soft in texture.

Demeylination post-myelin staining (Luxol fast blue)

  • Now, show a section of the same brain stained with Luxol fast blue, which turns myelin blue and Periodic acid-Schiff (PAS), which turns gray matter pink.
    • We see that the region of demyelination is pale; the contrast with the rest of the myelin is much easier to appreciate than in the unstained gross pathological section.

Chronic MS Histopathology

  • On histopathology, we see areas of chronic demyelination, axonal transection, as well as neuronal and glial cell death.
  • Neurodegeneration is believed to either be a primary, separate, process or a secondary process due to chronic inflammation.
  • It's thought that chronic inflammation leads to the production of free radicals (such as reactive oxygen and nitrogen species) that lead to complex biochemical derangements, including oxidative injury, mitochondrial dysfunction, protein misfolding, alterations in ion channel function along axons, and lack of trophic support from myelin – ultimately leading to axon and neuronal death.
    • Neuronal death can occur due to axon pathology that triggers retrograde degeneration or anterograde degeneration that leads to loss of neuronal connectivity.
    • Or it can occur as its own, separate poorly understood process: since neuronal death occurs at regions without underlying demyelination, a separate pathophysiological process makes intuitive sense.

Remyelination

Finally, show that acute MS demyelination can also recover in the form of remyelination.

  • Re-draw a neuron covered in thin sheaths of myelin.
  • Re-draw our histopathological insert with a pale blue in the former region of demyelination.

Chronic MS Pharmacotherapeutics

  • Consider that the goals of therapy at this time are a chronic reduction in inflammation, augmentation of remyelination, and suppression of neurodegeneration but that the agents that are available at these time are generally focused on the reduction of chronic inflammation.
  • With this information as a background, now we can now address the current pharmacotherapeutics of MS, which act via chronic immune modulation.

We'll divide the available medications by their modes of administration:

  • Injectable medications
  • Oral medications
  • Intravenous infusions

Injectable Medications

  • The injectable medications became available were the first to hit the market, they became available in 1993.
  • Generally, these are considered the least efficacious of the drugs now used but because they have been available for over twenty-five years and because of their well accepted safety profile, many patients remain on them.

Mechanisms of Action

Interferon-beta (IFN-beta)

  • First, introduce IFN-beta.
  • Indicate that it down-regulates pro-inflammatory lymphoctyes and up-regulates regulatory T-cells.

Glatiramer acetate (GA)

  • Next, introduce GA.
  • Indicate that it induces an anti-inflammatory T-cell response.

IFN-beta & GA

  • In our diagram, show that IFN-beta and GA act on lymphocytes.
    • Note that their mechanisms of action are far more complex than how we simplify them here and still not fully understood.

Side Effects

  • Common side effects for both of these drugs include injection site reactions.
  • Show that IFN-beta tends also can often produce flu-like symptoms, and depression.
  • Whereas indicate that GA can often cause a systemic allergic response.

Monitoring

  • Monitoring for IFN-beta includes:
    • Intermittent complete blood count (CBC) and Liver function tests (LFTs)
    • Thyroid testing
  • GA:
    • No specific monitoring is necessary for GA.

Oral medications

  • Three oral medications are currently available:
    • Teriflunomide
    • Dimethyl fumarate (DMF)
    • Fingolimod
  • On the whole, these medications are considered to be more effective than the injectables; fingolimod, specifically, is the most effective of the three.
  • As we'll see, however, it has widespread effects throughout the body and, thus, getting patients started on it is more challenging than with teriflunomide or dimethyl fumarate and its side effect profile is more worrisome.

Teriflunomide

Mechanism of Action

  • Indicate that teriflunomide reversibly inhibits the mitochondrial enzyme dihydroorotate dehydrogenase, which is fundamental to the de novo pyrimidine synthesis pathway, thus it targets proliferating lymphocytes.
  • Show a lymphocyte in the process of proliferating and indicate that teriflunomide blocks this rapid reproduction.

Side Effects

  • Indicate that teriflunomide is category X (it's highly teratogenic) and its presence in seminal fluid means that warning about its teratogenicity extends to male patients, as well.
  • Additional common side effects are hair thinning and diarrhea.

Monitoring

  • Prior to starting teriflunomide, the following tests are recommended:
    • CBC and CMP
    • Pregnancy test
    • TB testing.
  • LFTs are recommended every 6 months.

Dimethyl fumarate (DMF)

Mechanism of Action

  • Indicate that dimethyl fumarate (DMF) preferentially depletes CD8+ T-cells (more so than CD4+ T-cells). We recall that CD8+ T-cells outnumber CD4+ T-cells in MS, so there is good rationale for its use.
  • Show dimethyl fumarate inhibit CD8+ T-cells.

Side Effects

  • Indicate that a common side effect is flushing (aspirin can help treat this), along with GI upset, and lymphopenia.
  • DMF does confer a very low risk of progressive multifocal leukoencephalopathy (PML), which we address at the end.

Monitoring

  • CBC should be checked prior to starting DMF and periodically thereafter.

Fingolimod

Mechanism of Action

  • Indicate that fingolimod prevents lymphocyte egress from lymph nodes via modulation of lymphocyte sphingosine-1-phosphate (S1P) receptors.
    • This causes the lymphocytes to redistribute to secondary lymphoid tissues (eg, tonsils and spleen), out of circulation.
  • Show fingolimod prevent lymphocytes from leaving the lymph node.

Side Effects

  • Sphingosine-1-phosphate receptors are common throughout the body, so in combination with the lymphopenia that results from fingolimod, numerous side effects can occur.
  • Indicate that these risks include: varciella-zoster virus (VZV), macular edema, bradyrhythmia, and basal cell carcinoma.
  • There is a very low risk of PML with fingolimod, as well, albeit slightly higher than with dimethyl fumarate (we address this in detail at the end).

Monitoring

  • Because of the side effect profile, testing surrounding fingolimod is quite extensive, as follows:
    • CBC and LFTs as screening and periodically while on treatment.
    • Varicella zoster IgG (vaccinate patient, if non-immune), as opportunistic infections can arise from the lymphopenia (notably, varicella zoster infection and cryptococcal infection).
    • EKG and first-dose heart rate monitoring for bradyrhythmia
    • Ocular exam for macular edema as a screening, three months following initiation, and periodically thereafter.
    • Skin assessment periodically for basal cell carcinoma.

Intravenous Infusions

Natalizumab

Mechanism of Action

  • Indicate that natalizumab is a human monoclonal antibody to alpha4 integrin. It blocks lymphocyte migration across the blood-brain barrier.
  • Show natalizumab act along the blood-brain barrier to reinforce this point.

Side Effects

  • The risk of PML from natalizumab is the highest of the MS drugs that are commonly used and is its most notable side effect.

Monitoring

  • Prior to initiation and every 3 to 6 months, check:
    • Liver function tests (LFTs)
    • Anti-JC virus antibody

Ocrelizumab

Mechanism of Action

  • Indicate that ocrelizumab is a human monoclonal antibody to CD20, which causes depletion of B-cells that present the CD20 receptor.
  • Draw a B-cell presenting CD20 and show ocrelizumab attacking it.

Side Effects

  • Indicate that it's too early to report on the side effect profile of ocrelizumab (it only received FDA approval in March of 2017); there is concern that breast cancer may ultimately be considered a potential side effect.

PML

Progressive Multifocal Leukoencephalopathy (PML)

  • Finally, let's address progressive multifocal leukoencephalopathy (PML), which is a major potential adverse side effect of certain MS drugs.
  • The disease is a fairly rapidly progressive, eventually fatal disorder (typically within 6 months), if untreated.
    • Treatment involves immune reconstitution; typically via plasmapharesis and immunoadsorption.
  • It begins with infection of oligodendrocytes (so it's a white matter disorder, early-on). Patients manifest with ataxia, visual disturbance, encephalopathy, and a myriad of other potential neurological symptoms (given the diffuse nature of the disease).
  • Indicate that we categorize both dimethyl fumarate and fingolimod as having a low but real risk of PML.
    • The risk of PML with fingolimod is ~ 1/10,000 but other opportunistic infections (note that other opportunistic infections can also occur with fingolimod, including herpes zoster and cryptococcal infections).
    • At present time, DMF appears to confer less of a risk of PML than fingolimod but there is a concern that prolonged CD8+ T-cell suppression could lead to more PML over time.
  • Indicate that we categorize natalizumab as having a high risk of PML: 1/90 (in anti-JC virus positive patients) and 4/1,000, overall.
    • Anti-JC antibody testing helps risk stratify patients for the possibility of getting PML from treatment with natalizumab.

JCV (John Cunningham virus)

  • PML is exclusively due to JCV (John Cunningham virus), which is a strain of human polyoma virus.
  • Much of the population eventually is infected with JC virus but they remain asymptomatic, if immunocompetent. When people become immune suppressed, such as with immune modulating agents, the JC virus can enter the CNS and attack oligodendrocytes (hence it is an oligodendropathy: a white matter disease at onset).

PML Histopathology

  • On histopathology, intranuclear inclusions are observed within the oligodendrocytes, along with enlarged astrocytes and a sparse inflammatory response.

PML Gross Pathology & Radiography

  • On gross pathology and radiographic imaging, the PML lesions are characteristically large, confluent, necrotic and typically localize to the brain, itself (rather than the spinal cord).
  • There is destruction of myelin out of proportion to the axon damage, at least initially. * Eventually, however, axon degeneration ultimately occurs; as discussed previously, the myelin sheath has important metabolic effects on the maintenance and health of axons and when it is destroyed, the axons eventually fail.

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