SYTY KNOW ABOUT MS?

D A N C I N G W I T H T H E N E U R O L O G I S T S

W I L L I A M S B A E K M D FA A N
COI
• Speaker for AbbVie Pharmaceuticals
 P U B L I C AT I O N S
Baek W.S., Aypar U. Neurological manifestations of X-linked ichthyosis. Case Rep in Gen 2017.
Baek W.S. Sodium oxybate improves EDS, cataplexy, and lowers IL-2 receptor levels in a 12-year-old boy. ECNP 2017.
Baek W.S. Diagnosing hereditary ataxias.J Clin Review and Case Reports 2017, 1;1
Baek W.S., Elsea SH. Smith-Magenis Syndrome Treated with Ramelteon and Amphetaminedextroamphetamine. J Genet Disor Genet Rep 2016, 5:4
Baek W.S. Atypical absence epilepsy and migraines in mosaic trisomy 14 treated with topiramate: a case of FOXG1 overexpression? EC Neurology 3.3 2016: 396-401
Baek W.S. Histone deacetylase inhibitors as future disease-modifying therapy for Huntington’s disease. The J of So Cal Clinicians 2016
Baek W.S. Rufinamide adjunctive therapy reduced atypical absence seizures on EEG. Jacobs J of Clin Case Reports 2016; 2(3): 035
Baek W.S. Cross-bun sign characteristic of multiple systems atrophy. AJNR 2016
Baek W.S. Comfort measures for severe diffuse axonal injury: a patient’s last wish. Amer J of Bioethics Neuroscience, 2016; 7(1):64-8
Baek W.S. Intravenous Lipid Emulsion as an Immediate Antidote for Carbamazepine Toxicity. SRL Neurology & Neurosurgery 2015: 1(1): 002
Baek W.S. Iatrogenic upper trunk plexopathy persisting even a year after arthroscopic shoulder surgery. Mus & Nerv 2015
Baek W. S. Iatrogenic cerebral arterial and venous gas embolism leading to massive hemorrhage, herniation and death. Neurology: Clinical Practice, 2015; 5(6):528-530
Baek W.S. Recurrent facial baroparesis occurring on commercial flights in the US. J J Neur Neurosci. 2014, 1(1): 004
Baek W.S. NT-proBNP as a blood biomarker for Alzheimer’s disease. JSM Alzheimer’s Dis Related Dementia 2014, 1(1): 1003
Baek W.S. Isolated unilateral dorsal scapular nerve injury while playing football: CME case. Mus & Nerv 2014
Park MJ, Baek W.S. et al. Nasalance scores in normal-speaking Korean adults and children. Journal of Plastic, Recon & Aesthetic Surgery 2014; 67: 173-7
Baek W.S. Drummer boy’s palsy and bungee cord palsy: two cases of bona fide radial nerve palsies. CME case Mus & Nerv 2014
Baek W.S., Swenseid SS, Poon KY. Quality Care Assessment of Parkinson's Disease at a Tertiary Medical Center. Int J Neurosci. 2013; 123(4):221-225
Baek W.S. EMG-guided botulinum toxin injections for refractory myokymia in chronic inflammatory demyelinating polyradiculoneuropathy. Mus & Nerv 46; 4; 621–79
Baek W.S. Pregabalin resolves refractory aparathyroid paroxysmal kinesigenic choreoathetosis. Clinical Neuropharmacology 2012; 35(4):203
Baek W.S. Hoffman TL. Facioscapulohumeral muscular dystrophy: pitfalls in genetic testing. Muscle & Nerve 2012 Vol. 44; 4: 623–694
Baek W.S. Isolated medial antebrachial cutaneous sensory neuropathy Status-Post Brachioplasty. Mus & Nerv 2011 42; 4: 622–696
Baek W.S. Nitrous Oxide-induced severe sensorimotor polyneuropathy without pernicious or megaloblastic anemia. Mus & Nerve 2011 42; 4: 622–696
Baek W.S. Management of Alzheimer’s disease in the primary care setting: a prospective survey. Alz & Dementia: The J of the Alz Assoc 2010; 6(4): S327
Baek W.S. Hypertensive Encephalopathy with Infarcts status-post Hysterectomy. Electroen and Cl Neurophys/electromyog and Motor Control.120; S90-S90, 2009
Baek W.S. Botulinum Toxin A injections in medically-refractory post-stroke Holmes’ tremor. Electroenc and Cl neurophys/electromyogr and Motor Control.120; S83, 2009
Baek W.S, Kubba S.V. Cauda equina syndrome due to leptomeningeal carcinomatosis of the ovary. Gynecol Oncol. 2008
Baek W.S, Desai NP. ALS: Pitfalls in the diagnosis, Prac Neurology 2007 7: 74-81
Baek W.S, Sheean GL. Occupation dystonia of the truncal muscles in a bricklayer, Movement disorders 2006: 22; 2: 284-285
Baek W.S, Sheean GL. Complete remission induced by rituximab in refractory seronegative, MuSK-positive MG, J Neuro Neurosurg Psych 2006
Baek W.S, Rezania K. Tarlov Cysts masquerading neuropathy, Arch Neurol 2006; 63(12):1804-5
Baek W.S, Pytel P, Undevia S, Rubeiz H. Spinal Cord Metastasis of a non-NF1 MPNST: a rare manifestation of a rare tumor, J Neurooncol. 2005 Sep; 74(2):183-5
Baek W.S., Chohan S, Pytel P, Dalvi A. An atypical presentation of PAN: bilateral foot drop and central retinal artery occlusion, J of Clin Neurosci 2004
McManus M., Baek W.S., Golden J.A. Axon Mediated Inhibitory Interneuron Migration, Journal of Neuropath and Exp Neurology 2004
 AGENDA DE JOUR

1.What is MS?
2.Who usually gets MS?
3.How does MS present?
4.How is MS diagnosed?
5.How is MS treated?
W H AT I S M S ?
• The most common chronic inflammatory, demyelinating and neurodegenerative disease of the
CNS in young adults.
• A heterogeneous, multifactorial, immune-mediated disease that is influenced by both genetic and
environmental factors. Filippi et al. Multiple Sclerosis 2018

• Affects 900 000 people in the US.

• Typically presents in young adults (mean age of onset, 20-30 years)
• Can lead to physical disability, cognitive impairment, and decreased QOL
McGinley et al. JAMA 2021

• CIS(clinically isolated syndrome): 1 attack, objective evidence of 1 lesion

MS GENETICS
• Genes involved in MS pathogenesis:
- HLA DR2: the strongest genetic factor in MS susceptibility
- APOE4: associated with higher lesion load, more rapid progression
- Caspase-2: may predict favorable response to DMTs
• Lifetime risk of developing MS:
- A child born from a mother with MS: 5%
- An identical twin: 30%
 Young(late teens-40s)

Women, women, women

WHO
U S U A L LY
GETS MS? Usually Caucasian or African
American, some Hispanic

Rare: Asian, male, elderly

HOW DOES MS PRESENT?

Transverse myelitis Stroke-like symptoms

Optic neuritis

Numb from waist down constant painless numbness

Unilateral visual loss
Paraparesis with weakness of subacute
with pain on ocular movement onset, lasting several months
Bladder incontinence

Rarely NOT with

diffuse body pain
vertigo(imbalance) headache
diplopia isolated bowel incontinence

Pirko I et al. Arch Neurol 2004

HOW IS MS DIAGNOSED?
• Signs, symptoms AND abnormal MRI
• Signs: APD, INO, hopefully some UMN signs
• Symptoms: classic history and demographics!
• Brain and C spine MRI w/wo: normal MRIs effectively EXCLUDE MS

- Barkhof MRI criteria Barkof F et al. Brain 1997

• LP not mandatory
• If the MRI is unclear: VEPs, other lab tests(to rule out), LP

- OCBs can be negative in MS

- OCBs an be positive in sarcoidosis, SLE, APLA, Sjӧgren, HIV, viral encephalitis, ADEM, NMO, ALD, CADASIL
• ANAs are frequently positive in MS
• Revised McDonald criteria(clinical + MRI) Polman CH et al. Ann Neurol 2005
 W H AT ’ S O N T H E D I F F E R E N T I A L F O R
MS?

Other demyelinating
RIS(radiologically
Antiphospholipid Susac syndrome NMO(usually history and isolated syndrome)
antibody syndrome MRI findings are
Sarcoidosis no signs/symptoms of MS
different),anti-MOG, late
but MRI looks like MS
onset hereditary

MS wannabes Cf. ADEM: presents with

Tumor(if tumefactive
radiculopathies, fever, headache(different
MS)
fibromyalgia, PMR from MS)
R E D F L A G S T H AT I T ’ S N O T M S
• Hearing loss, esp bilateral
• Onset at extremes, <10 or >50
• CSF protein>100mg/dL
• CSF WBC>50mm3
• Presence of CSF PMNs
• Negative MRI
• Negative CSF(~10% is negative)
• Progressive-onset course(10-15% of cases)
• Unilateral lesions on brain MRI
• Coexisting systemic or autoimmune disorders
• Prominent PNS signs
• Significant psychiatric history
• Marked deficits without objective signs or MRI abnormalities
1981

2021
MRI FINDINGS OF MS

• Multiple, white matter(cf. cortical), oval, perpendicular, asymmetric, callosal, optic nerve, ring-
enhancing
• ‘Dawson’s fingers’: callosal lesions perpendicular to ventricles
• High on T2/FLAIR(MS lesions)
• Low on T1(black holes)
M U LT I P L E
SCLEROSIS
T U M E FA C T I V E M S
SOMETIMES IT’S HARD TO
DIAGNOSE BASED EVEN ON MRI
34/M. Fulminant MS vs
ADEM?

22/F. NMO
Diroxel fumarate
2020
(Vumerity®)
RMS CIS SPMS
Ofatumumab
2020
(Kesimpta®)
RMS
MS DMTS(DISEASE-MODIFYING
T R E AT M E N T )
• Self-injectables: Platform(ABCR), Ofatumumab(Kesimpta®)
- Ofatumumab(Kesimpta®): proven superior to Aubagio, SQ form of Ocrevus
20mg SQ at weeks 0, 1, 2, then 40mg SQ q mo
Cf. Glatopa(generic Copaxone) SQ x3/wk
Plegridy® (peginterferon-beta 1a, from Avonex) SQ q 2 wks
• Orals:
• Infusions: Natalizumab(anti-VLA4, Tysabri), Alemtuzumab(Lemtrada),
• Vit D: ALWAYS check VD levels in MS, goal >30
MS ORAL MEDS: S1P RECEPTOR
M O D U L AT O R S
MOA: sequesters autoreactive T cells in LN, decreasing release into peripheral blood

- Fingolimod(Gilenya®)

Dose: 0.5mg qd

S/E: lymphopenia, 1st and 2nd deg AVB(3%, 1st dose monitoring, contraindicated with Ia or III anti-arrhythmics), macular edema(0.4%), VZV

CIx: MI, CHF, stroke, TIA, Mobitz type II second-deg or third-deg AVB, SSS, baseline QTc>500ms, ILD

- Siponimod(Mayzent®)

Dose: 2mg qd

Requires CYP2C9 genotype testing prior

CIx: CYP2C9 *3/*3 genotype)

- Ozanimod(Zeposia®): also for UC

Dose: 0.92mg qd

Cix: Fingolimod’s + severe OSA, MAOI

- Ponesimod(Ponvory®)

Dose: titrate from 2mg to 20mg/D over 2 weeks

 MOA: promote anti-inflammation (T cells)

Dimethyl fumarate(Tecfidera®)

Dose: 120mg bid x 1 week, then 240mg bid

MS ORAL S/E: lymphopenia, flushing(baby ASA), indigestion(fatty

MEDS:NRF2 foods)
A C T I VA T O R S Diroxel fumarate(Vumerity®)

Dose: 231mg bid x 1 week, then 462mg bid

S/E: lymphopenia
MS ORAL MEDS
• Cladribine(Mavenclad®)

MOA: interfere with DNA synthesis and repair, leading to DNA strand breaks and cell death
Dose: 1-2 pills/day for 4-5 days per year based on Bwt (1.75mg/kg/year)
CIx: HIV, active chronic infection(Tb, hepatitis), active malignancy, immunocompromised, moderate-severe renal
impairment(CCL<60mL/min), pregnancy/breastfeeding
S/E: rash, fever, headache, N/V/D, lymphopenia
• Teriflunomide(Aubagio®)

MOA: selectively and reversibly inhibits dihydro-orotate dehydrogenase, decreasing proliferation of activated T and B cells without causing cell
death
WARNING: hepatotoxicity(acute liver failure requiring transplant), embryofetal toxicity
Dose: 7-14mg once daily
Slow elimination: use cholestyramine or activated charcoal
CIx: severe hepatic impairment, pregnancy, breastfeeding, childbearing age without contraception, with leflunomide
S/E: ALT, alopecia, diarrhea, DRESS(drug reaction with eosinophilia and systemic symptoms), peripheral neuropathy, HTN, ILD, pancreatitis
in children
MS INFUSIONS
• Ocrelizumab(Ocrevus®): proven superior to Avonex
MOA: Binds to CD20(+) B cells ADCC, complement-mediated lysis
Dosing: 300mg IV on day 1 and 14, then 600mg IV q 6 mo
• Natalizumab(Tysabri®)
MOA: against α-4 integrins on circulating inflammatory T cells(blocks T cell migration across BBB)
S/E: PML
• Alemtuzumab(Lemtrada®)
MOA: targets CD52 on both B and T cells, leading to depletion of both CD4+ and CD8+ T cells, resulting in sustained reduction of T cells>B cells
Dosing: 2 courses(1st course: 12mg/D on 5 consecutive days, 2nd course: 12mg/D on 3 days 1 year later)
VZV vaccination in VZV Ab neg patients at least 6 weeks prior to 1st course, check TSH q 3 months
WARNING: serious, sometimes fatal ITP, anti-GBM, must be administered in setting for severe reactions, may cause increased risk in
malignancy(thyroid cancer, melanoma, lymphoproliferative: annual skin exams), REMS
CIx: HIV
S/E: rash, headache, lymphopenia, suicidal ideation(0.6%)
• Mitoxantrone(Novantrone®)
MOA: intercalates with DNA, has anti-proliferative effects on T cells, suppresses humoral immunity
Dosing: 12mg/m2 once every 3 months
S/E: CMP
ANTI-CD20S
M S S Y M P T O M AT I C T R E AT M E N T

Fatigue
Gait Cognition Spasticity, muscle spasms
Dalfampridine(Ampyra) Baclofen, Botulinum
Modafinil
25FWT nothing works toxin injections
Adderall

Neuropathic pain Urinary frequency

Erectile dysfunction Depression/anxiety
Oxybutynin(Ditropan),
Gabapentin, Pregabalin Tolterodine(Detrol)
Viagra, Cialis SSRIs
Pain mgt Botox

AFO, cane, walker, W/C,

Antibiotics for UTIs
scooter
 T N F - Α A N D I L - 6 L E V E L S I N M U LT I P L E
SCLEROSIS ON
D I M E T H Y L F U M A R AT E :
A RETROSPECTIVE STUDY

William S. Baek, MD1, Song Zhai2, and Xinping Cui, PhD2

1 Dept of Neurology, Parkside Medical Group, Upland, CA, USA

2 Department of Statistics, University of California at Riverside, Riverside, CA, USA

 INTRODUCTION

•There is growing interest in studying biomarkers to individualize treatment Harris and Sadiq, 2014

•One is tumor necrosis factor-alpha (TNF-α), a pro-inflammatory cytokine produced by activated macrophages. TNF-α negatively correlates

with Expanded Disability Status Scale (EDSS) scores Uysal et al., 2014

•Interleukin-6 (IL-6) is both a pro- and anti-inflammatory cytokine that inhibits TNF-α Scheller et al., 2011, Rodriguez et al., 1994

•Hautecoeur et al. have shown that both TNF-α and IL-6 are increased (p < 0.007) during relapses, concluding that TNF-α could be a relapse

marker while IL-6 might reflect the global immune activity in MS Hautecoeur et al., 1997

•Polachini et al. also found that TNF-α and IL-6 were elevated compared with controls in RRMS Polachini et al., 2014

•Moreover, interferon β-1b decreases TNF-α and increases IL-6 in MS Brod et al., 1996
 INTRODUCTION(2)

•DMF(Tecfidera®) has been FDA-approved for RRMS since 2013.

•DMF decreases TNF- α and IL-6 in activated microglia and astrocytes in vitro (Wilms et al., 2010) and down-

regulates TNF-α-induced IL-6 secretion in lung fibroblasts Seidel et al., 2010

•However, little is known about how DMF works in vivo, especially with no evidence of disease activity (NEDA).

•Hence, we conducted a retrospective study on patients receiving DMF, with TNF-α and IL-6 assessed as part of

routine care.
 OBJECTIVES

A. To investigate TNF-α and IL-6 in MS NEDA patients on DMF

B. To see if any correlation between TNF-α, IL-6, EDSS, vitamin D, age, duration of DMF therapy,

or the number of MRI lesions exists

 M E T H O D S : PAT I E N T S

• This was a six-year retrospective study of patients seen by a single neurologist (WSB) from January

1, 2014, to October 31, 2019.

• WSB confirmed participants’ diagnosis of MS, or a clinically isolated syndrome (CIS) based on the

2017 McDonald diagnostic criteria.

• After we applied the inclusion and exclusion criteria, we collected the final data from a total of 11

study participants, with participants having six visit-points during this six-year retrospective study.
 INCLUSION CRITERIA

1. Patients aged 18 or above with a new or pre-existing diagnosis of either MS or CIS

2. Patients with laboratory data performed at baseline and every 3-4 months afterwards (at least three times),

and MRI prior to starting DMF and afterwards (at least twice)

3. Patients who were naïve to MS medications or had been off treatment for at least one year prior to starting

DMF
 EXCLUSION CRITERIA

1. Those still on multiple sclerosis disease-modifying therapy at the time of the initial visit

2. Those who missed their follow up visits, lab tests, MRIs or discontinued DMF

3. Patients with concurrent infectious or inflammatory/autoimmune conditions

4. Patients who relapsed or developed new MS lesions on MRI during the study period
 STUDY DESIGN

• If a patient had visited the clinic several times in one year, we calculated the mean number of

clinical records among these visits and used them in the subsequent analysis.

• Occasional laboratory values were missing as the laboratories had failed to perform the correct

tests.

• We used Multiple Imputation by Chained Equations (MICE) to replace the missing values
Azur et al., 2011, White et al., 2011
 S TAT I S T I C A L A N A LY S I S
• We performed longitudinal data analysis using linear mixed-effects models. Specifically, we treated TNF-α and IL-
6 as separate quantitative endpoints. Laird and Ware,
1982

• For the fixed effects model used to describe how the mean values change within this population, we included
within the full model the duration of DMF therapy, the patient’s age, CRP levels, absolute lymphocyte
count(ALC), vitamin D levels, baseline number of T1 black holes, baseline number of T2 lesions, and baseline
EDSS scores, as well as the interactions between the duration of DMF therapy and the other variables.
• To account for heterogeneity of participants’ baseline levels of TNF- and IL-6, we also included random, subject-
specific intercepts and slopes.
• While constructing the prediction model for the within-subjects analysis, we considered different variance-
covariance structures among the six visit-points including compound symmetry, first-order autoregression and
spatial power, then selected the optimal model according to the Akaike information criterion (AIC) Sakamoto et al., 1986
 S T A N D A R D P R O T O C O L A P P R O VA L

• This study was approved by the Institutional Review Board of the University of California at Riverside.
 R E S U LT S

• A total of 84 study participants were started on DMF either as de novo or second-line therapy.
After we applied exclusion criteria, we included 11 participants in the data analysis.
• Ten were female and one was male, with a mean age was 46.9 years.
• The mean age of MS symptom onset was 33.3 years, with a mean time from symptom onset to
diagnosis of 6.6 years.
• The mean baseline EDSS score was 2.5.
 R E S U LT S ( 2 )

• On baseline brain MRI, participants had a mean of 21.6 T2-FLAIR lesions and 6.4 T1-
hypointense lesions.
• Mean values for baseline laboratory studies included CRP of 1.78 mg/ml (SD 2.57 mg/ml), ALC
of 1542/µL (SD 513/µL), and vitamin D level of 35.64 ng/ml (SD 21.97 ng/ml).
Figure 1: Graphs depicting how the interaction between variables affect TNF-𝜶 levels. TNF-
𝛼 levels are affected by the interaction between the duration of DMF therapy and A. age, B. CRP
levels, C. ALC, D. vitamin D levels, E. baseline T1 black holes, F. baseline T2 lesions, and G.
baseline EDSS score. The terms high and low here refer to higher or lower than the population
mean.
Figure 2: Graph of TNF-𝜶 levels from all patients while on DMF therapy. The population
mean at each time point is shown in red.
Figure 3: Graphs depicting how the interaction between variables affect IL-6 levels. IL-6
levels are affected by the interaction between the duration of DMF therapy and A. age, B. CRP
levels, C. ALC, D. vitamin D levels, E. baseline T1 black holes, F. baseline T2 lesions, and G.
baseline EDSS score. The terms high and low here refer to higher or lower than the population
mean.
Figure 4: Graph of IL-6 levels from all patients while on DMF therapy. The population mean
at each time point is shown in red.
TNF-Α LEVELS ARE AFFECTED BY THE DURATION OF
DMF THERAPY, PATIENT AGE, AND CRP LEVELS

• Taking TNF-α as a quantitative endpoint, and AIC as the model selection criteria, the optimal model would
include the duration of DMF therapy, patient age, CRP levels, the interaction between the duration of DMF
therapy and CRP levels, as well as the random intercept and slope
Table 1: Linear mixed-effects model, taking TNF-𝜶 as the endpoint.

Fixed Effects

Value p value*

Intercept 1.18 < 0.00

Duration of DMF therapy -0.22 < 0.00

(years)

Patient age (years) 0.01 0.10

CRP levels (mg/ml) -0.08 0.07

Duration of DMF therapy × 0.03 0.02

CRP levels

Random Effects

Patient ID Time Patient ID Time Patient Time

1 -0.03 2 -0.07 3 -0.03

4 -0.07 5 0.14 6 -0.12

7 -0.02 8 -0.01 9 -0.01

10 0.04 11 0.16

*significance level = 0.10

• The variance-covariance structure within each patient is formulated as the first-order autoregressive structure, which assumes that the
further away between two visit-points the less correlation there will be.

•The following mathematical formulas that are derived from Table 1 numerically characterize the relationship between TNF- levels and the

duration of DMF therapy, age, and CRP levels.

 TNF- 0.01 age

Age affects TNF- levels regardless of the duration of DMF therapy: the older the subject was, the higher the TNF- levels were. In other

words, when age increases by 1 year, TNF- levels increase by 0.01pg/ml.

 TNF- (- 0.08 + 0.03 duration of DMF therapy) CRP levels

The effect of CRP levels on TNF- levels depends on the duration of DMF therapy. That is, during the first 3 years of DMF therapy, a higher

CRP level implies a lower TNF- level; however, when beyond 3 years of DMF therapy, a higher CRP level implies a higher TNF- level.

 TNF- (- 0.22 + 0.03 CRP levels) duration of DMF therapy

TNF- levels decreased significantly according to the duration of DMF therapy: the longer the duration of DMF therapy, the lower the TNF-

α levels were. However, the rate of decrease depended on the CRP levels; a higher CRP level implied a lower rate of decrease.
•In summary, the duration of DMF therapy, age, and CRP all significantly affected TNF- levels at a

significance level of 0.10, whereas baseline T1 black holes, baseline T2 lesions, baseline EDSS scores,

ALC, or vitamin D levels did not.

•As shown in Table 1, TNF- levels decreased significantly during the DMF therapy as a whole (p <

0.00).

•Furthermore, a likelihood ratio test demonstrated that random effects were significant within this

model (p = 0.01), which means that the rates of decrease in TNF- levels among different patients

deviated significantly from the population-averaged rate of decrease.

IL-6 LEVELS ARE AFFECTED BY THE DURATION OF
DMF THERAPY, PATIENT AGE, AND VITAMIN D
LEVELS.

• Taking IL-6 as a quantitative endpoint, and AIC as the model selection criteria, the optimal model would
include the duration of DMF therapy, age, and the interaction between time and vitamin D levels, as well as
the random intercept and slope
Table 2: Linear mixed-effects model, taking IL-6 as the endpoint.

Fixed Effects

Value p value*

Intercept 19.67 0.01

Duration of DMF therapy 2.21 0.08

(years)

Age (years) -0.27 0.09

Duration of DMF therapy × -0.04 0.07

Vitamin D levels (ng/ml)

Random Effects

Patient ID Time Patient ID Time Patient Time

1 5.57 2 -0.50 3 -0.26

4 -0.54 5 1.66 6 -0.86

7 1.22 8 -6.02 9 -2.37

10 0.32 11 1.25
•The variance-covariance structure within each patient is formulated as the first-order autoregressive structure.

•The following mathematical formulas derived from Table 2 numerically characterize the relationship between IL-6 levels and the

duration of DMF therapy, age, and vitamin D levels:

 IL-6 ∝ - 0.27 × age

Age affects IL-6 levels regardless of the duration of DMF therapy: the older the subject was, the lower the IL-6 levels were. In other

words, when age increases by 1 year, IL-6 levels decrease by 0.27 pg/ml.

 IL-6 ∝ (- 0.04 × duration of DMF therapy) × vitamin D levels

IL-6 level decreases when vitamin D levels increase. In addition, this rate increases with the duration of DMF therapy.

 IL-6 ∝ (2.21 – 0.04 × vitamin D) × duration of DMF therapy

IL-6 levels increased significantly according to the duration of DMF therapy: the longer the duration of DMF therapy, the higher the

IL-6 levels were. However, the rate of increase depended on the vitamin D levels; higher vitamin D levels implied a lower rate of

increase.
•In summary, the duration of DMF therapy, age, and vitamin D level all significantly affected

IL-6 levels at a significance level of 0.10, whereas baseline T1 black holes, baseline T2

lesions, baseline EDSS scores, CRP, or ALC did not.

•Of note, although IL-6 levels increased significantly during the DMF therapy as a whole (p

= 0.08 < 0.10), this was not as significant as the decrease in TNF- levels (p < 0.00).

•Furthermore, a likelihood ratio test implied that random effects were not significant within

this model (p = 0.12). In other words, the rates of increase in IL-6 levels among different

patients during DMF therapy did not deviate significantly from each other.
 DISCUSSION

•In this six-year retrospective study we found that levels of both TNF-α levels and IL-6 were

affected by the duration of DMF therapy and patient age.

•TNF-α levels were also affected by CRP levels, while IL-6 levels were affected by vitamin D

levels. DMF appeared to decrease TNF-α levels while increasing IL-6 levels.

•We created mathematical formulas to calculate these values based on several variables, a process

which to our knowledge has not previously been reported in the published literature.
 DISCUSSION(2)

•Medina et al. have reported that only MS patients with NEDA showed a significant decrease in

TNF-α levels Medina et al., 2018

•However, our results indicate that the rate of decrease depends on the CRP levels, which has not

been previously reported. This might have been due to fact that CRP cutoff values differ among

laboratories and are reported solely as less than such values (without providing an exact number),

which might have skewed the data.

 DISCUSSION(3)
•The fact that TNF-α levels increase with age has been previously reported, which was confirmed again in our study.

Bruunsgaard et al., 2000

•Previous reports on how age affects IL-6 levels have been somewhat conflicting, with some studies showing that IL-6 levels

increase with age (Bruunsgaard et al., 2000, Ashtari et al., 2019), and others demonstrating no increase at all (Beharka et al., 2001).

•In our study cohort, IL-6 levels decreased with age. We also discovered that CRP levels significantly affected TNF levels,

whereas baseline T2 lesions, T1 lesions, baseline EDSS scores, ALC, or vitamin D levels did not.

•As a pro-inflammatory cytokine, TNF-α is known to stimulate the release of CRP.

 DISCUSSION(4)

•The duration of DMF therapy, patient age, and vitamin D levels all significantly affected IL-6 levels, whereas baseline T1

lesions, baseline T2 lesions, baseline EDSS scores, or ALC did not.

•Our findings were consistent with the results shown by Taşdemir et al., who reported no correlation between the number of

baselines T2 lesions and IL-6 levels Taşdemir et al., 2010

•Our data showing that IL-6 levels decreased with an increase in vitamin D levels were consistent with previous reports

Hashemi et al., 2018

•Moreover, this rate increases with the duration of DMF therapy, which has not been previously reported. We also

discovered that IL-6 levels increased significantly according to the duration of DMF therapy: the longer the duration of

DMF therapy, the higher the IL-6 levels were.

 DISCUSSION(5)

• An increase in IL-6 levels produced by classically stimulated monocytes in RRMS patients on

DMF therapy has been previously reported Fiedler et al., 2017, Chuluundorj et al., 2014, Sarchielli et al., 1997

• It has been suggested that DMF-induced IL-6 has the potential to act in an
anti-inflammatory/protective manner on the mixed phenotype cells present in MS lesions Fiedler et al.,
2017

• The role of IL-6 in multiple sclerosis remains somewhat controversial, with some investigators
suggesting that IL-6 signaling may increase MS disease activity (Schneider et al., 2013),while others
characterizing IL-6’s dual role as both a pro- and anti-inflammatory cytokine as not entirely
detrimental in MS(Fuster and Walsh, 2014, Göbel et al., 2018).
 DISCUSSION(6)

•In this study, we found that the decrease in TNF-α levels correlated more strongly with the duration of DMF

therapy than the increase in IL-6 levels. For this reason, TNF-α may be a more promising biomarker than IL-6 for

monitoring MS patients who are on DMF therapy.

•The substantial variation in the rates of decrease in TNF- levels among different patients suggests an opportunity

for future studies to identify which subgroup of patients will have greater rates of decrease in TNF- levels.

•We believe TNF-α has the potential to become a clinically valuable serum biomarker that could allow a more

individualized approach to enhancing the efficacy of DMF therapy.

 S T U D Y L I M I TAT I O N S

•We were unable to establish cause and effect between TNF-α and CRP levels, and IL-6 and vitamin D levels.

•Another limitation of our study is that the final sample size was small with only 11 patients, hence we chose a

relatively flexible significance level 0.1 instead of 0.05 Fisher, 1960, Perezgonzalez, 2015

•Furthermore, our linear mixed-effects model implies that IL-6 levels decrease with age in MS, which is inconsistent

with the previous studies (Bruunsgaard et al., 2000, Ashtari et al., 2019, Beharka et al., 2001), which also might also be due to sample size.

•Lastly, there was no age-matched untreated group as a control.

Q U E S T I O N S , C O M M E N T S ?
THE END