eCase Challenge

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Case Presentation

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Beth is a 37-year-old white female. She presents to the clinic for various neurologic symptoms.
Over the course of several years, she noticed various changes including, a new stumbling and
tripping easily. Her vision also seemed to get worse and then better for the past 3 years.

Three months ago, she was under a lot of work stress, and then became sick with a cold.
Coinciding with the cold, she felt weak and clumsy with her hands, and felt tired all the time.
After a few more days of work, she suddenly became numb with some “pins and needles”
sensation on her right side.

MRI scan taken at that time revealed a multifocal white matter disease with various areas of
increased T2 signal in both cerebral hemispheres.

She remains weak and numb on the right side; otherwise, she has no known medical
conditions; she does not take any medications.

In a review of systems, you note several problems related to her suspected MS. She has
decreased finger dexterity and weakness of the hands bilaterally. She also complains of mild
short-term memory difficulties.

Biometrics:
▪ Height: 5 feet 1 inches
▪ Weight: 123 lbs
Vital Signs:
▪ Heart rate: 59 bpm
▪ BP: 111/72 mmHg
▪ Respirations: 18/minute
Past Medical History:
▪ Seasonal allergies
▪ Tubal ligation 5 years ago
Family History:
▪ Father, hypertension, CAD
▪ Sister, breast cancer, lumpectomy, previous chemotherapy, no current treatment
Social History:
▪ Non-smoker
▪ Alcohol use: prior - social/on occasion (2 glasses of wine on weekends)
▪ Occupation: Owner/manager stationary store
▪ Spouse: married, one daughter
Current Medications:
▪ Multivitamin daily
Known Allergies:
▪ No known drug allergies
▪ Seasonal allergies
Recent Laboratory Findings:
▪ TSH: 1.2 mIU/mL [within normal limits]
▪ HbA1C: 5.2%

In this patient with likely multiple sclerosis (MS) diagnosis, she has described and continues to
have many symptoms. This leads to the first clinical question.

© 2020 American Academy of PAs and Medical Logix, LLC. All rights reserved. 2
Question #1

Which of the following clinical findings would be most consistent with a relapse of multiple
sclerosis?

A. Unilateral optic neuritis

B. Bilateral optic neuritis
C. Complete gaze palsy
D. Subacute cognitive decline

Beth is a 37-year-old patient with likely multiple sclerosis diagnosis due to separation of her
neurological symptoms in space and time, supported by MRI findings.

She has already experienced many neurological symptoms. Differentiating between relapses
and pseudo-relapse is useful for describing and prognosticating her disease. Patients can find
these terms confusing, however.

Firstly, patients should understand that many of these terms have the same meaning: attack,
bout, exacerbations, flare, relapse.

Explaining these terms with the analogies presented in the white board explainer videos can be
helpful. When differentiating between pseudo-attack (pseudo-relapse) and attack (relapse), the
pseudo-attack is similar to the signal flickering in and out, where a wire may have to be moved
in just the right way to get the signal to go through properly. The wire is still working, the wire is
still intact, but it isn’t transmitting the signals properly.

Clinically, exacerbations or pseudo-relapses may present as flare ups of old symptoms and may
be triggered by various causes, including stress, fatigue or infections. Relapses or evidence of
disease activity may include:1–5
• Focal, localized, new clinical manifestations
• New symptoms lasting ≥24h
• New MRI lesions
• New contrast-enhancing lesions

Sometimes though, the line between relapse and exacerbation is often not clear.

When differentiating between relapses and symptoms suggesting another etiology, perhaps
more serious, typical presentations include acute unilateral optic neuritis and double vision due
to an internuclear ophthalmoplegia or sixth nerve palsy (usually in patients younger than 40
years). However, atypical or red flag presentations include bilateral optic neuritis or unilateral
optic neuritis with poor visual recovery, and complete gaze palsy or fluctuating
ophthalmoparesis.6

It is also important to stress to patients that every time a new symptom arises, this is not the
same as a new attack. There is a difference between that flickering signal, and a completely
new attack/relapse.
Case Continues

© 2020 American Academy of PAs and Medical Logix, LLC. All rights reserved. 3
After explaining the diagnosis of multiple sclerosis to Beth, you begin to ask her about her
preferences and values for treatment. She is still quite young and wishes for relatively
aggressive treatment but is still quite concerned about the safety profile of the numerous
medication choices.

This brings us to our next clinical question.

Question #2

Which of the following agents, based on current evidence, is NOT considered to be a higher-
efficacy disease-modifying therapy?

A. Alemtuzumab
B. Natalizumab
C. Ocrelizumab
D. Teriflunomide

Again, to aid in the discussion of MS therapies with patients. The cat and wires analogy is
continued. The strategies for managing the immune effects on the neurons (the cats chewing on
the wires) directly informs the relative efficacy and safety of these options. More aggressive
strategies tend to be more effective, but they come with their own safety considerations that are
not included in the less effective medications.

MS therapies, broadly, affect the immune system to provide their effect. These mechanisms or
strategies inform the relative efficacy and safety of the agents.

Within the context of the analogies presented in the white board videos, there are four cat
(immune system) management strategies:
• Retraining cats (immunomodulators): Teaching cats what to attack and what not to
attack. But it is difficult to train a cat. (e.g., glatiramer acetates, interferons)
• Restraining cats (natalizumab): Lock the study door and make it impossible for a cat to
get in
• Sequestering cats (lymphocyte sequesters [S1P]): Prevent the cat population from
moving through the house freely; keep them sequestered in areas without wires
• Euthanizing cats (B-cell depleting therapies): Cull the cat population and grow a new cat
population (immune system remodeling agents: e.g., cladribine, alemtuzumab)

MS therapies are grouped based on their relative potency:

Low-potency treatments:
• Interferons
• Glatiramer acetate
• Teriflunomide

Intermediate-potency treatments:
• Dimethyl fumarate
• Diroximel fumarate
• S1P receptor modulators
• Cladribine

© 2020 American Academy of PAs and Medical Logix, LLC. All rights reserved. 4
High-potency treatments:
• Alemtuzumab
• Natalizumab
• Ocrelizumab
• Ofatumumab

Thus, the correct answer to this question is D.

Beth would like to pursue a highly effective therapy but would like to hear more about the safety
profile of these medications. This brings us to our next clinical question.

Question #3

Which of the following agents is most associated with potential rebound activity when
discontinued?

A. Dimethyl fumarate
B. Natalizumab
C. Ofatumumab
D. Rituximab

Rebound is defined as an increase in disease activity beyond what the patient experienced in
the past. Rebound is common with natalizumab1 and S1P modulators (e.g., fingolimod7). This
rebound phenomenon may be reduced with the use of steroids.8 Another approach is to avoid
the washout period and quickly switch to other DMTs.

Thus, the correct answer to this question is B.

Again, by way of analogy, rebound on discontinuation may be thought of as after restraining the
cats for a while, if you suddenly remove the door, the cats can go wild and damage the speaker
wires.9

Other safety considerations must be included when discussing medications. This leads to the
next clinical question.

Question #4

Which of the following is a safety concern associated with the use of ocrelizumab?

A. Progressive multifocal leukoencephalopathy (PML)

B. Stroke risk
C. Congestive heart failure
D. Suicidal ideation

Many agents are associated with an increased risk of JCV infection and potentially PML. These
include S1P agents, natalizumab and ocrelizumab. JCV/PML not associated with use of
glatiramer acetate.

When explaining this risk to patients, one can describe it as such: Some pests, that the cat
would normally clear out, can grow in the stereo (brain) - John Cunningham (JC) virus.

© 2020 American Academy of PAs and Medical Logix, LLC. All rights reserved. 5
When people have this virus in their bodies, and taking natalizumab, ocrelizumab or S1P agents
(e.g., fingolimod, siponimod), JC virus can rise up in the brain and cause other kinds of damage
leading to different kinds of neurological symptoms; unchecked, severe neurologic symptoms
and death (progressive multifocal leukoencephalopathy [PML]).10 Patients taking these agents
undergo a very thorough risk evaluation and a mitigation strategy (REMS), including screening
for the presence of JC virus prior to use.

Thus, the correct answer to this question is A.

To describe the relative risk of PML from natalizumab compared with S1P modulators,
natalizumab (closing the study door/restraining cats) and B-cell depleting therapies (euthanizing
cats) may have the complication of an infestation of mice/PML – a study-specific/brain-specific
disease. S1P modulators, on the other hand, restrict/sequester the cells in lymph nodes so
there are fewer cells migrating, but the ones that are there can get in or out. PML can still occur,
but less frequently than with natalizumab.

Overall, the absolute risk of PML is very low.

Note that there is still a risk for other infections, though at very low rates: zoster, cryptococcus,
etc.

Case Continues

Beth seems to be leaning towards the use of ocrelizumab for her MS, but she has not
completed her vaccination series for SARS-CoV-2 (COVID-19 infection). She asks about the
use of this medication and if it will interfere with the efficacy of vaccination.

This brings us to our final clinical question.

Question #5

What does current research say about the effect of B-cell depleting therapies on SARS-CoV-2
vaccine efficacy?

A. No effect on either humoral response or T cell response

B. Reduction of both humoral response and T cell response to near zero
C. Reduction of humoral response
D. Increase in humoral response and reduction of T cell response

Amit Bar-Or and his colleagues11 found that patients taking anti-CD20 antibody (aCD20)
monotherapy had a significant reduction in antibodies to the receptor binding domain-specific
spike protein and had attenuated memory B-cell responses (humoral responses). This effect
was improved with longer duration from last aCD20 treatment and extent of B cell reconstitution.
All patients with MS treated with aCD20 still produced antigen-specific CD4 and CD8 T-cell
responses after vaccination.

In a similarly designed trial by Gadani and colleagues12, the humoral responses were attenuated
in people taking anti-CD20 therapy compared to people with MS who were either on other
DMTs or were not on treatment. Humoral responses were detected in 22/39 (56.4%)
participants on anti-CD20 and in 59/63 (93.6%) participants on no DMTs or on other DMTs. Still,

© 2020 American Academy of PAs and Medical Logix, LLC. All rights reserved. 6
most patients had a good T-cell response, even if they did not have a great humoral (B-cell)
response. In a subset (n=88; 87%), T-cell responses were detected in 76/88 (86%), including
32/33 (96.9%) participants on anti-CD20 therapies.

While it is still early to know the full significance of this data, based on this information some
recommendations may be considered.

For patients who are going to start B-cell depleting MS therapy, but have not started it yet, try to
encourage them to get their vaccine series completed beforehand so that they aren't affected by
this medication, unless their disease is very aggressive.

For patients already taking these therapies, recommend delaying the infusion when it is safe to
do so, or try to back up the vaccination relatively close to when their next infusion is due to
hopefully give them the best chance possible of making a response. These patients qualify for a
third dose of the primary vaccine series (due to immunosuppression).

Returning to the analogies used, there are many cat groups (Siamese cats, domestic cats,
calico cats), and while the B-cell depleting therapies may kill all of one group (B-cells), you still
have the remaining groups of cats (T-cells) to respond to a vaccine.

Case Continues

Beth opts for treatment with a highly effective therapy, in this case ocrelizumab. She is aware of
the safety profile of this medication based on your discussions. You screen for JC virus and
proceed with the recommended monitoring (REMS).

Based on your discussions, she has a fulsome understanding of this diagnosis and treatment
options. Similarly, she understands the ideas of relapse, pseudo-relapse, and progression. You
schedule her for follow-up in 1 month to review how the infusion went and to monitor for safety
issues and laboratory values.

Conclusions

Patient engagement in their own health has been described as “the blockbuster drug of the
century.” Clinicians that treat multiple sclerosis (MS) can improve clinical outcomes by
incorporating patients in management decisions. This is especially important in a chronic illness
such as multiple sclerosis (MS), which requires lifelong treatment.13
Explaining the diagnosis and treatment of multiple sclerosis can be challenging, though crucial.
This program aims to offer tools to help communication while describing how these tools may be
used.

The specifics of this case cover many issues including high-potency treatments, rebound and
various safety concerns.

To briefly reiterate, high-potency treatments include: alemtuzumab, natalizumab, fingolimod,

ocrelizumab, and ofatumumab. Rebound phenomenon is common with natalizumab and
fingolimod.

Many agents are associated with an increased risk of JCV infection and potentially PML: these
include S1P agents, natalizumab, and B-cell depleting therapies.

© 2020 American Academy of PAs and Medical Logix, LLC. All rights reserved. 7
Lastly, due to the COVID-19 pandemic many questions on the use of vaccination and MS
treatments have arisen. Based on early research the humoral (B-cell) response is diminished
compared with controls, but the T-cell response is still robust (though slightly diminished). This
program covers some possible recommendations for patients considering treatment or already
on treatment who wish to be vaccinated.

References

1. AAN. Practice Guideline Recommendations Summary: Disease-modifying Therapies for Adults with
Multiple Sclerosis. Published April 23, 2018. Accessed October 24, 2020.
https://www.aan.com/Guidelines/Home/GuidelineDetail/898
2. Fisniku LK, Brex PA, Altmann DR, et al. Disability and T2 MRI lesions: a 20-year follow-up of
patients with relapse onset of multiple sclerosis. Brain. 2008;131(Pt 3):808-817.
doi:10.1093/brain/awm329
3. Río J, Rovira A, Tintoré M, et al. Relationship between MRI lesion activity and response to IFN-beta
in relapsing-remitting multiple sclerosis patients. Mult Scler. 2008;14(4):479-484.
doi:10.1177/1352458507085555
4. Sormani MP, Rio J, Tintorè M, et al. Scoring treatment response in patients with relapsing multiple
sclerosis. Mult Scler. 2013;19(5):605-612. doi:10.1177/1352458512460605
5. Prosperini L, Gallo V, Petsas N, Borriello G, Pozzilli C. One-year MRI scan predicts clinical
response to interferon beta in multiple sclerosis. Eur J Neurol. 2009;16(11):1202-1209.
doi:10.1111/j.1468-1331.2009.02708.x
6. Brownlee WJ, Hardy TA, Fazekas F, Miller DH. Diagnosis of multiple sclerosis: progress and
challenges. Lancet. 2017;389(10076):1336-1346. doi:10.1016/S0140-6736(16)30959-X
7. Barry B, Erwin AA, Stevens J, Tornatore C. Fingolimod Rebound: A Review of the Clinical
Experience and Management Considerations. Neurol Ther. 2019;8(2):241-250.
doi:10.1007/s40120-019-00160-9
8. Fuentes-Rumí L, Hernández-Clares R, Carreón-Guarnizo E, et al. Prevention of rebound effect after
natalizumab withdrawal in multiple sclerosis. Study of two high-dose methylprednisolone schedules.
Multiple Sclerosis and Related Disorders. 2020;44:102311. doi:10.1016/j.msard.2020.102311
9. Sorensen PS, Koch-Henriksen N, Petersen T, Ravnborg M, Oturai A, Sellebjerg F. Recurrence or
rebound of clinical relapses after discontinuation of natalizumab therapy in highly active MS
patients. J Neurol. 2014;261(6):1170-1177. doi:10.1007/s00415-014-7325-8
10. Baldwin KJ, Hogg JP. Progressive multifocal leukoencephalopathy in patients with multiple
sclerosis. Curr Opin Neurol. 2013;26(3):318-323. doi:10.1097/WCO.0b013e328360279f
11. Bar-Or A, Calkwood JC, Chognot C, et al. Effect of ocrelizumab on vaccine responses in patients
with multiple sclerosis. Neurology. 2020;95(14):e1999-e2008.
https://n.neurology.org/content/neurology/95/14/e1999.full.pdf
12. Gadani SP, Reyes-Mantilla M, Jank L, et al. Discordant humoral and T cell immune responses to
SARS-CoV-2 vaccination in people with multiple sclerosis on anti-CD20 therapy. EBioMedicine.
2021;73:103636. doi:10.1016/j.ebiom.2021.103636
13. Rieckmann P, Boyko A, Centonze D, et al. Achieving patient engagement in multiple sclerosis: A
perspective from the multiple sclerosis in the 21st Century Steering Group. Mult Scler Relat Disord.
2015;4(3):202-218. doi:10.1016/j.msard.2015.02.005

© 2020 American Academy of PAs and Medical Logix, LLC. All rights reserved. 8