REVIEW OPEN ACCESS

Lymphopenia and DMTs for relapsing formsof MSConsiderations for the treating neurologist

Edward J Fox MD PhD Guy J Buckle MD MPH Barry Singer MD Vibhuti Singh PhD and Aaron Boster MD

Neurology Clinical Practice February 2019 vol 9 no 1 53-63 doi101212CPJ0000000000000567

Correspondence

Dr Boster

aaronbosterohiohealthcom

AbstractPurpose of reviewTo provide neurologists with an update on the proposed mecha-nisms of action (MOAs) of disease-modifying therapies (DMTs)for the treatment of relapsing MS and their effect on peripheralblood leukocytes in order to inform treatment decisions

Recent findingsDMTs have vastly differing MOAs including effects on peripheralblood leukocyte counts particularly lymphocytes The clinicalimplications of changes in lymphocyte counts need to be un-derstood in the context of the underlying MOAs of each respectiveDMT with treatment tailored to individual patient needs

SummaryDMTs can alter lymphocyte counts subsets activation and distri-bution and thus can influence immune surveillance Serial moni-toring of total leukocytes and absolute lymphocyte counts (ALCs) isadvisable in patients receiving DMTs ALCs should be interpreted regarding expected immu-nologic changes and individual patient characteristics Any decision to switch DMTs shouldconsider these factors along with drug efficacy safety and effect on quality of life

MS is a chronic immune-mediated demyelinating CNS disorder1 associated with de-velopment of neurologic deficits and subsequent accumulation of physical and cognitivedisability2 Around 23 million people worldwide and 400000 in the USA have MS3 witha higher incidence in women4 Although there are regional variations the prevalence of MS inthe US in 2012 was 1492 per 100000 individuals4 Relapsing forms of MS (RMS) account forover 80 of all MS cases at onset and thus comprise a substantial proportion of MS casesunder a neurologistrsquos care1

There is strong evidence indicating that infiltration of autoreactive immune cells into the CNSparticularly CD4+ and CD8+ T cells plays an important role inMS pathogenesis5 In addition

Multiple Sclerosis Clinic of Central Texas (EJF) Central Texas Neurology Consultants Round Rock TX MS Institute at Shepherd Center (GJB) Atlanta GA The MS Center forInnovations in Care (BS) Missouri Baptist Medical Center St Louis MO Indicia Medical Ltd (VS) Part of the Fishawack Group of Companies Hyderabad India and OhioHealthMultiple Sclerosis Center (AB) Riverside Methodist Hospital Columbus OH

Funding information and disclosures are provided at the end of the article Full disclosure form information provided by the authors is available with the full text of this article atNeurologyorgcp

The Article Processing Charge was funded by Novartis Pharmaceuticals Corporation

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CC BY-NC-ND) which permits downloadingand sharing the work provided it is properly cited The work cannot be changed in any way or used commercially without permission from the journal

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InfographicNPuborgNCP023382

Copyright copy 2019 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology 53

a growing body of evidence has highlighted the involvementof B cells as important contributors to MS pathogenesis5ndash8

The proposed mechanisms of action (MOAs) of variousdisease-modifying therapies (DMTs) for the treatment ofpatients with RMS generally involve some form of immu-nomodulation or lymphocyte depletion involving T cellsB cells or both DMTs target lymphocytes by modulatingtheir activation proliferation or cytokine secretion or byreducing their trafficking across the bloodndashbrain barrier58

As this review indicates a nuanced approach is necessary forinterpreting changes in complete blood counts observed inrelation to DMTs There is no single ldquonormalrdquo lymphocytelevel for each individual DMT and it is recommended thatdue consideration be given to expected changes vs changesthat potentially signal unfavorable clinical outcomes It is alsoworth noting that lymphopenia can occur in patients withMS that is unrelated to treatment with DMTs9ndash11

Proposed MOAs and evidence oflymphopenia for currentlyavailable DMTsSeveral injectable oral and infusible DMTs have been ap-proved for the treatment of RMS based on clinical trial evi-dence demonstrating reductions in MS relapse frequencymagnetic resonance imaging disease activity and ongoing dis-ability accumulation Many of these DMTs result in a decreasein circulating T and B lymphocytes However it is important tonote that circulating lymphocytes represent only a small pro-portion (2) of the total population thus they may not bean accurate indicator of the bodyrsquos total lymphocyte pool andfunction1213 Furthermore fluctuations in blood lymphocytesseldom correlate with changes in composition and numberof lymphocyte subsets in other lymphoid and non-lymphoidorgans13 Therefore blood lymphocytes provide limited in-formation on an individualrsquos immune status13

A basic understanding of the underlying MOAs of DMTs andtheir effects on the immune system can help to inform themanagement of patients with RMS The currently understoodMOAs of DMTs and their known effects on lymphocyte sub-sets and the immune system are summarized in the table andfigure and discussed further in the following section of thisreview

Beta IFNsNumerous studies have demonstrated that anti-inflammatoryproperties of the beta interferons (IFNs) are mediatedthrough downregulation of pro-inflammatory CD4+ andCD8+ memory T cells memory B cells and a concomitantincrease in regulatory T cells (Tregs)14151851 Dose-relatedreductions in all cell lineages predominantly leukocyteshave been observed with IFNs with the most notable effect

seen in total leukocyte and lymphocyte counts14 It has beenestimated that approximately two-thirds of patients treatedwith IFNs will develop cytopenialymphopenia whichgenerally resolves 34 months after treatment initiation52

Glatiramer acetateThe synthetic polymer glatiramer acetate (GA) does notaffect absolute lymphocyte counts (ALCs)53 Instead GAappears to promote anti-inflammatory cytokine shifts inCD4+ and CD8+ T cells restores Tregs and decreases bothmemory B and T cells2054 Consequently GA is infrequentlyassociated with leukopenia and when it does occur it isgenerally mild in nature2255

DaclizumabDaclizumab binds to the alpha subunit (CD25) of the high-affinity interleukin-2 (IL-2) receptor expressed on activatedT cells and modulates IL-2 signaling resulting in an expansion ofCD56BRIGHT natural killer (NK) cells and a reduction in proin-flammatory activated T cells25 In clinical trials daclizumab wasassociated with reductions in total lymphocyte counts and T andB cell counts of le10 which were reversible following treatmentdiscontinuation and a low overall incidence of lymphopenia24ndash26

FingolimodFingolimod affects lymphocyte migration to secondarylymphoid organs via down-modulation of sphingosine 1-phosphate receptor 1 on lymphocytes preventing egress ofC-C chemokine receptor type 7+ (CCR7+) lymphocytesnaıve and central memory T cells and memory B cells fromlymph nodes714 Fingolimod does not sequester effectorT cells lacking CCR7 in lymph nodes56 It has been shownthat most patients who receive fingolimod can generate animmune response against both new and recalled antigensand their lymphocyte functions remain largely intact32

TeriflunomideTeriflunomide an immunomodulator selectively and reversiblyinhibits the mitochondrial enzyme dihydroorotate de-hydrogenase and specifically targets proliferating lymphocytes(while sparing resting or slowly dividing cells) resulting indecreases in CD4+ and CD8+ T cells memory B cells and NKcells28 Overall teriflunomide is associated with only infrequentmild lymphopenia and neutropenia which tends to reverse withongoing treatment or following treatment discontinuation10

Dimethyl fumarateThe small molecule dimethyl fumarate (DMF) results inselective depletion of CD8+ over CD4+ T cells34 In clinicaltrials with DMF a reduction in ALC of approximately 30

54 Neurology Clinical Practice | Volume 9 Number 1 | February 2019 NeurologyorgCP

Table Overview of the disease-modifying therapies in RMS

Treatment Patient-years ofdrug exposure

Proposed mechanism ofaction

PK profile Effect on circulatingleukocytes

Effect on immunesystemvaccine response

Rate of recovery oflymphocytes

Rate of seriousinfections

IFNs (Betaseron RebifAvonex Extavia Plegridy)

Figures not readilyavailablemdashwidelyused for over 20years14

Recombinant cytokine14 1 month after treatment Leukopenia(lymphopenia)14

NA NA

Downregulation of immunerecognition molecules such asMHC Class II antigens co-stimulatory molecules andadhesion molecules14

Considerable reduction vsbaseline in memory B cells15

Normal humoral andcellular response toinfluenza vaccine1617

Promotes a TH1 (pro-inflammatory)ndashTH2 (anti-inflammatory) shift in cytokineresponse14

Decreases CD4+ and CD8+ T cellsproducing IFN-gamma andIL-418

Reduction of lymphocytemigration across thebloodndashbrain barrier14

Potential stimulation of neuronalgrowth factor release14

Glatiramer acetate(Copaxone)

gt200000019 Synthetic polymer that diminishes theexpression of MHC Class IImolecules deactivates monocytesandmacrophages14

Tmax 15ndash30 min20 After 3 mo of treatment21 Rare leukocytosis ormild leukopenia14

NA 1ndash222

Promotes a TH1 (pro-inflammatory)ndashTH2 (anti-inflammatory) shift in cytokineresponse14

Limited PK data inpatients with MS20

Major increase in regulatoryCD8+ T cells over baseline

Decreases responseto influenza vaccines(pandemic andseasonal)23

Exerts neuroprotective effects14 Treatment activates thetransformation of conventionalCD4+CD25 T cells to regulatoryCD4+CD25+ T cells14

Daclizumab (Zinbryta) 5214 (clinical trialsonly data cutoff2016)24

Humanized monoclonalantibody14

MedianTmax 5ndash7 days25

Increase in CD56BRIGHT NK cells(06 of lymphocytes atbaseline to 36 at end oftreatment) Increaseapparent by week 426

Potential lymphopeniaand leukopenia(generally mild)24

8ndash12 weeks afterdiscontinuation25

3 vs 0 for placebo26

CD25 antagonist that modulates IL-2signaling leading to an expansionof CD56BRIGHT NK cells which arethought to eliminate pathogenicT cells that contribute toinflammation in MS1426

Time to steady state3ndash4 months25

7ndash10 decrease in CD4+

and CD8+ T-cell countsat week 5226

Continued

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Table Overview of the disease-modifying therapies in RMS (continued)

Treatment Patient-years ofdrug exposure

Proposed mechanism ofaction

PK profile Effect on circulatingleukocytes

Effect on immunesystemvaccine response

Rate of recovery oflymphocytes

Rate of seriousinfections

T12 21 d25 CD4+CD8+ ratio remainedconstant26

Teriflunomide (Aubagio) 162000 (as ofOctober 2017)27

Active metabolite ofleflunomide14

Median Tmax 1ndash4hours10

During first 6 weeks oftreatment10

Potential mildlymphopenia andneutropenia1014

May resolve withongoingtreatment or afterdiscontinuation10

14 (7 mg) and 22(14 mg) vs 21 forplacebo10

Pyrimidine synthesis inhibitionby inhibiting DHODH andthereby reducing replicationof high-aviditylymphocytes1428

Time to steady state3 months10

15 mean decrease in WBCsmainly lymphocytes andneutrophils

Patients able to mounta response toneoantigen (rabiesvaccine) immuneresponse weaker vsplacebo-treatedpatients29

T12 18 and 19 daysfor 7 and 14 mgrespectively10

Fingolimod (Gilenya) 480000 (as ofAugust 2017)30

Sphingosine 1-phosphateantagonist7

Tmax 12ndash16 h9 After 1 mo of treatment31 Lymphocyteredistribution14

1ndash2 mo afterdiscontinuation9

23 vs 16 forplacebo9

Redistribution of lymphocytesin secondary lymphoidtissue7

Time to steady state1ndash2 mo9

CD3+ T cells decreased from78 to 39 (50 overallreduction from baseline)

Immune responsesmounted to tetanusand influenza32

T12 6ndash9 d9 CD4+ T cells decreased from59 to 12 (80 overallreduction from baseline)

Reduced responserates vs placebo-treated patients32

CD19+ B cells decreased from8 to 3 (63 overallreduction from baseline)

CD4+CD8+ ratio decreasedfrom 36 to 06 (83 overallreduction from baseline)

NK cells increased from 11 to51 (364 overall increasefrom baseline)

Dimethyl fumarate(Tecfidera)

gt464000 (as ofJanuary 2017)33

Fumaric acid methyl ester14 Median Tmax2ndash25 h11

After 12 mo of treatment34 Potential leukopenia(lymphopenia)1114

4 wk afterdiscontinuation inclinical trials(lower thanbaseline)11

20 vs 20 forplacebo11

Continued

56Neu

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Table Overview of the disease-modifying therapies in RMS (continued)

Treatment Patient-years ofdrug exposure

Proposed mechanism ofaction

PK profile Effect on circulatingleukocytes

Effect on immunesystemvaccine response

Rate of recovery oflymphocytes

Rate of seriousinfections

Activation of Nrf2 signalingpathway14

T12 1 hour11 30 decrease in meanALC

Adequate humoralresponse to tetanusvaccine response ratecomparable to IFN-treated patients35

Prolongedlymphopenia afterdiscontinuation iscommon in clinicalpractice36

Protects against oxidative stress-induced cellular injury inneurons1437

44 decrease in CD3+ T cells

Promotes a TH1 (pro-inflammatory)ndashTH2 (anti-inflammatory) shift in cytokineresponse1437

55 decrease in CD8+ T cells

39 decrease in CD4+ T cells

36 increase in theCD4+CD8+ ratio

38 decrease in CD19+ B cells

54 decrease in eosinophils

Natalizumab (Tysabri) 559749 (as ofFebruary 2017)38

Humanized monoclonal anti-α4integrin antibody14

Time tosteady-state 24wks39

3ndash6 mo after startingtreatment40

Diminished immunesurveillance in theCNS14

CNS reconstitution in6ndash12 mo841

3 for natalizumaband placebo39

Inhibits α4β1 (VLA-4)14 T12 11 days39 Considerable increase in WBClymphocytes and lymphocytesubsets (CD3+ CD3+CD4+CD3+CD8+ CD19+CD16+CD56+)

Normal humoralresponse to influenzavaccine adequateresponse to tetanusand KLH4243

Increase inlymphocytes persistsfor 30 months40

Restricts the extravasation oflymphocytes into CNS14

Greater increase from baselinein B cells (320) vs T cells (192fold) or NK cells (188 fold)

Alemtuzumab(Lemtrada)

6500 (clinicaltrials only datacutoff October2013)44

Humanized immunoglobulinG1 monoclonal anti-CD52antibody8

T12 2 weeks42 After 7 days of treatment45 Lymphopenia45 After discontinuation45 3 vs 1 for IFN45

Results in rapid lysis oflymphocytes46

998 decrease inCD4+ T cells

Normal vaccine responsesto influenza DTPmeningococcus andpneumococcus47

B cells 6 months

985 decrease inCD8+ T cells

CD4+ T cells up to1ndash2 y

Continued

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was observed in the first year of treatment11 In additionprolonged lymphopenia (ge6 months) was seen in 22 ofpatients57 One month after stopping treatment meancounts increased but did not return to baseline levels in allpatients11

NatalizumabNatalizumab an anti-α4 integrin monoclonal antibody(mAb) affects lymphocyte migration to the CNS Distinctfrom other mAbs it leads to considerable increases in CD4+

and CD8+ T cells CD19+ B cells and NK cells with no effecton the CD4+CD8+ T-cell ratio in the periphery but a re-duction in the CNS4041 The increases in ALC followingnatalizumab infusion likely occur as a result of increasedrelease of CD34+ progenitor cells from bone marrow as wellas impaired egress of lymphocytes from the periphery withconcomitant reduction in lymphocytes in the CSF and no-table reduction in the CSF CD4+CD8+ ratio3958 Afterdiscontinuation circulating lymphocytes usually return tobaseline levels within 16 weeks the CD4+CD8+ rationormalizes within 6 months83941

AlemtuzumabAlemtuzumab an anti-CD52 mAb causes near-completedepletion of circulating lymphocytes dramatic drops inCD4+ and CD8+ T cells CD19+ B cells and NK cells havebeen observed after treatment followed by variable re-constitution of leukocyte subpopulations generally over6ndash12 months4559 During alemtuzumab treatment ALCdecreases rapidly after the first infusion however all celltypes including memory CD4+ and CD8+ T cells start torecover within the first month post-infusion with a selectivedelay in CD4+ T cell reconstitution (taking le2 years tonormalize vs CD8+ T cells which return to normal after 3months of treatment) B cells are restored approximately 6months post-discontinuation845

OcrelizumabOcrelizumab an anti-CD20mAb leads to pronounced B-celllymphopenia that has been shown to persist for a median of72 weeks after last infusion49 Following the first infusionB cell counts are reduced within 2 weeks and remain de-pleted throughout ongoing treatment B cells have beenshown to recover to baseline levelslower limit of normal 25years after discontinuation in 90 of patients49Ta

ble

Ove

rview

ofthedisea

se-m

odifyingtherap

iesin

RMS

(con

tinue

d)

Trea

tmen

tPatient-ye

arsof

dru

gex

posu

rePro

pose

dmec

han

ism

of

action

PKpro

file

Effect

oncirculating

leuko

cytes

Effect

onim

mune

system

vac

cineresp

onse

Rateofreco

very

of

lymphocy

tes

Rateofse

rious

infections

CD8+

Tcells2

ndash3mo

Ocrelizu

mab(O

crev

us)

646

7(clin

ical

trials

onlya

sofJune

2016

)48

Human

ized

immunoglobulin

G1

monoclonal

anti-CD20

antibody4

9

T 122

6d49

Within

14day

softrea

tmen

tStudiesongo

ing

Med

ianof72

wk

(ran

ge27

ndash17

5wk)

afterdisco

ntinuation49

13

vs29

forIFN50

Res

ultsin

antibody-dep

enden

tlysisofBce

lls45

Dec

reas

esim

mature

and

mature

Bce

lls49

AbbreviationsALC

=ab

solute

lymphocyte

countDHODH=dihyd

roorotate

deh

ydroge

nas

eDMT=disea

se-m

odifyingtherap

yDTP

=diphtheriatetan

uspertussisF

DA=Fo

odan

dDru

gAdministrationIFN

=interferonIL=

interleu

kinK

LH=ke

yhole

limpet

hem

ocyan

inM

HC=majorhistoco

mpatibility

complex

NA=notap

plicab

leN

K=naturalk

illerP

K=pharmac

okineticR

MS=relapsingform

sofMS

T max=timetake

nto

reac

hmax

imum

conce

ntrationT

12=timerequired

fortheco

nce

ntrationto

fallto

50T

H=ThelperV

LA-4

=ve

rylate

antige

n-4W

BC=whitebloodce

lls

DMTs alter normal immune

responses and thus have the

potential to increase infection risk

58 Neurology Clinical Practice | Volume 9 Number 1 | February 2019 NeurologyorgCP

Clinical implications of lymphopeniaDMTs alter normal immune responses and thus have thepotential to increase infection risk However rates of seriousinfections reported in clinical trials are low (1ndash3) andsimilar between DMTs (table) Nevertheless there are someimportant differences between DMTs with respect to the riskof some serious opportunistic infections including pro-gressive multifocal leukoencephalopathy (PML) a de-myelinating disease associated with John Cunningham virus(JCV) infection Ongoing clinical and postmarketing safetystudies continue to collect information on infections inpatients receiving DMTs

Serious opportunistic infections associatedwith DMTsExtensive experience with GA and IFNs has not elicitedsafety concerns with respect to opportunistic infections orPML to date neither teriflunomide daclizumab nor ocre-lizumab has been associated with increased risk of opportu-nistic infections or PML in the RMS population14254960

However further long-term data are needed for ocrelizu-mab61 Daclizumab was voluntarily withdrawn from themarket following reports of inflammatory encephalitis andmeningoencephalitis62

Fingolimod has been associated with opportunistic infectionsincluding herpes viruses and cryptococcal infections14 In clin-ical trials 2 patients died of herpetic infections and cases offatal cryptococcal meningitis and disseminated cryptococcalinfections have been reported in the postmarketing setting9

The overall risk of PML not attributed to prior natalizumabtreatment remains very rare and is estimated to be112000patients As of August 2017 15 fingolimod-treated patients

were reported to have developed PML in the absence ofnatalizumab treatment in the preceding 6 months30 Howeverthese cases of PML were not associated with sustained grade 4(ALC lt02 times 109L) lymphopenia93061 An additional 4 casesof PML were later reported63

DMF-associated lymphopenia and PML have been a recentarea of focus CD8+ T lymphocytes which are likely criticalto defend against JCV64 are selectively depleted by DMFand their sustained reduction may result in an increased riskof developing PML34 To date one case of PML in a patientwith prolonged lymphopenia has been reported in a clinicaltrial11 and 4 cases have been reported in the postmarketingsetting in the presence of lymphopenia (lt08 times 109L)persisting for gt6 months1161

Natalizumab prescribing information indicates a general in-creased risk of developing infections39 and the risk of PML isknown to be higher for natalizumab (approximately 4 in1000 patients) than other DMTs increasing with treatmentduration (gt24 months) prior immunosuppressant exposureJCV antibody positivity and older age (gt44 years)396165 Asof February 2017 there have been 711 cases of PMLreported in patients with MS exposed to natalizumab witha mortality rate gt2038 The mechanisms underlying PMLdevelopment in natalizumab-treated patients remain un-clear it is assumed that impaired immunosurveillance in theCNS and mobilization of premature B cells infected by JCVinto the CNS may be involved61

Although no cases of PML following alemtuzumab treatmenthave been reported in patients with MS several cases ofListeria-associated infections during or soon after an

Figure Simple schematic depicting the general effects of selected DMTs on lymphocytes

The mechanisms of action of each DMT have not been fully elucidated in relapsing MS the depiction shown in this schematic with respect to effects onlymphocytes is based on currently available evidence Alemtuzumab is a humanized immunoglobulin-1 monoclonal anti-CD52 antibody that results in rapidlysis of lymphocytes42 Daclizumab is a humanized monoclonal anti-CD25 antibody that leads to CD56BRIGHT expansion via interleukin-2 modulation andconsequently to activated T-cell depletion14 Dimethyl fumarate is believed to exert its lymphopenic effect through activation of the Nrf2 pathway whichleads to induction of the anti-inflammatory stress protein HO-1 and consequently apoptosis of primarily CD8+ T cells834 Fingolimod is a sphingosine 1-phosphate (S1P) agonist after binding to and activating S1P1 fingolimod acts as a functional antagonist and prevents CCR7+ lymphocytes including naıve andcentral memory T cells and B cells from exiting lymph nodes78 Natalizumab is a humanized monoclonal anti-α4 integrin antibody that binds α4β1 integrin(very late antigen-4 [VLA-4]) and prevents lymphocytes from crossing the bloodndashbrain barrier (BBB) and entering the CNS14 Ocrelizumab is a recombinanthumanizedmonoclonal antibody directed against CD20-expressing B-cells it results in antibody-dependent cellular cytolysis following cell surface binding toB lymphocytes49 Teriflunomide inhibits de novo pyrimidine synthesis in rapidly dividing cells by inhibiting the enzyme dihydroorotate dehydrogenase(DHODH) causing a cytostatic effect on activatedproliferating T and B cells14

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 1 | February 2019 59

alemtuzumab treatment cycle have emerged in the post-marketing setting14 In clinical trials with alemtuzumab anti-viral prophylaxis reduced the frequency of herpes simplexinfections

Together these studies provide evidence that for the ma-jority of currently available DMTs there is no obvious linkbetween ALC and overall risk of opportunistic infectionsNevertheless continuous assessment of infection risk beforeduring and after administering DMTs is advisable and hasprofound clinical relevance given the link between MSexacerbations and infection66 To minimize infection riska comprehensive analysis of patient characteristics is re-quired for deciding on the optimal DMT including anyhistory of infectious disorders prior exposure to immuno-suppressants age and immune status For example patientswith low baseline lymphocyte counts and women with lowbody mass index may be at particular risk of developingclinically significant lymphopenia with fingolimod67 Inpatients receiving natalizumab prior immunosuppressantuse has also been associated with increased risk of PML68

and the recent American Academy of Neurology (AAN)practice guidelines on DMTs in MS state that a discussionregarding switching to a DMT with a lower risk of PMLshould take place for patients who are or become JCVantibody-positive while receiving natalizumab69 It is im-portant that healthcare providers look beyond lymphocytecount and remain vigilant to detect clinical signs andsymptoms in order to act swiftly in cases of opportunisticinfection

Lymphopenia and relationship withDMT efficacyBecause lymphocytes appear to be important contributorsto MS pathology elucidating the significance of DMT-induced lymphopenia and predicting which patients are atrisk of serious or opportunistic infections and who mightbenefit most from certain treatments are important forclinical decision-making Based on currently available datathere does not appear to be a link between lymphopeniaand DMT efficacy although such a link cannot be excludedgiven the complex mechanisms involved Despite long-standing clinical experience with IFN-beta immunologicmarkers that predict treatment efficacy have not beenidentified51 Similarly lymphopenia associated with DMFtreatment was not predictive of good clinical response orbreakthrough MS activity36 and no association betweenthe degree of lymphopenia and clinical outcomes was ob-served in patients treated with fingolimod70 Additionallyearlier evidence of IL-21 and differential lymphocyte re-constitution as potential biomarkers for relapse risk afteralemtuzumab treatment has not been validated71

Advances are being made towards establishing clinicallyrelevant markers of treatment response in RMS with neu-rofilaments representing a particular focus72 However inthe absence of reliable biomarkers close patient monitoring

and comprehensive patient education are of paramountimportance

Alternative dosing strategies toaddress lymphopeniaWith the exception of prolonged lymphopenia with DMFlymphopenia alone is not a signal to switch treatments or reducedosage in the majority of cases Rather lymphopenia may be anexpected consequence of the MOA of several DMTs and doesnot necessarily signify clinically significant loss of immunityNevertheless some physicians have devised alternative dosingstrategies to reduce lymphopenia risk A recent observationalstudy reported that fingolimod-associated lymphopenia couldbe mitigated by utilizing an every-other-day dosing regimenhowever there was a considerable increase in risk of relapse ornewmagnetic resonance imaging lesions Furthermore it is alsocurrently unknown whether alternate-day dosing has any ad-ditional effect on overall safety outcomes73

Switching DMTsSuspending or switching between DMTs may become nec-essary when patients fail to respond to therapy or whenconcerns emerge about actualpotential adverse events (suchas opportunistic or recurrent infections hepatotoxicity renalinsufficiency and cardiovascular diseasesmdashsee individualproduct labels) When switching between therapies it isimportant to consider both MOA and duration of action(table) of each therapy and understand the risks and benefitsassociated with each To avoid inadvertent additive treat-ment effects ALC monitoring and an optimal washout pe-riod should be elucidated for each drug-switchingcombination a long washout period may cause disease re-bound and a shorter period may be associated with safetyissues due to the synergetic effect of more than one drug onthe immune system74 No evidence-based guidelines forrecommended washout periods between DMTs currentlyexist and clinical practice varies widely The recent AANpractice guidelines on DMTs in MS make no recom-mendations for switching in cases of lymphopenia69 As eachtreating physician has their own approach to patient man-agement such as low lymphocyte counts that would promptdiscontinuation switching DMTs due to lymphopenia ismore likely to be based on personal protocols rather than setguidelines Monitoring of normalization of lymphocytecounts after DMT switches may help guide sequence timing

With the exception of prolonged

lymphopenia with DMF lymphopenia

alone is not a signal to switch

treatments or reduce dosage in the

majority of cases

60 Neurology Clinical Practice | Volume 9 Number 1 | February 2019 NeurologyorgCP

The presence of lymphopenia following initiation of DMTsknown to cause cell lysis or redistribution is not usually suf-ficient to warrant switching drugs or reducing dosageHowever per theDMF prescribing information interruptionof treatment should be considered in patients with lympho-cyte counts less than 05 times 109L persisting for more than 6months Although fingolimod treatment was interrupted inpatients with ALCs lt02 times 109L in the pivotal clinicaltrials75ndash77 post-marketing safety analysis and further studieshave not shown a clear correlation between the degree oflymphopenia and opportunistic infections78 The prescribinginformation contains no language regarding the necessity fordiscontinuation of fingolimod for lymphopenia howeverdue to treatment interruptions in the pivotal clinical trialsinformation on patients with ALCs lt02 times 109L who con-tinued fingolimod therapy is limited

To conclude a nuanced approach is proposed where theunderlying MOA of the DMT and key patient character-istics are considered There might not be a ldquonormalrdquo-lymphocyte count for patients with RMS on DMTs theimplications of any changes in lymphocyte count need to beunderstood in the context of the underlying MOA of pre-scribed DMTs and treatment tailored to individual patientneeds

Author contributionsEJ Fox draftingrevising the manuscript G Buckledraftingrevising the manuscript study concept or designanalysis or interpretation of data B Singer draftingrevising the manuscript data acquisition study concept ordesign analysis or interpretation of data V Singh draftingrevising the manuscript A Boster draftingrevising themanuscript

Study fundingMedical writing and editorial assistance in the developmentof this manuscript were provided by Vibhuti Singh PhD atIndicia Medical Ltd part of the Fishawack Group of Com-panies This service was supported by Novartis Pharma-ceuticals Corporation East Hanover NJ

DisclosureEJ Fox serves on scientific advisory boards for AcordaBayer Biogen EMD Serono Genentech Roche NovartisSanofi Genzyme and Teva has received funding for travelandor speaker honoraria from Acorda Biogen EMDSerono Genentech Roche Novartis Sanofi Genzyme andTeva serves as a consultant for Bayer Biogen EMD SeronoGenentech Roche Novartis Sanofi Genzyme and TevaNeuroscience serves on speakersrsquo bureaus for Acorda Bio-gen EMD Serono Genetech Roche Novartis Sanofi Gen-zyme and Teva receives research support from AbbVieAllergan Biogen Celgene Chugai EMD Serono Gen-entech Roche Mallinckrodt MedDay Novartis SanofiGenzyme Teva Neuroscience TG Therapeutics and Na-tional Multiple Sclerosis Society and has participated

in medico-legal cases GJ Buckle has received funding fortravel andor speaker honoraria from Biogen-Idec CelgeneEMD-Serono Genentech Genzyme- Sanofi Novartis andTeva serves as a consultant for Biogen-Idec Celgene EMD-Serono Genentech Genzyme- Sanofi Novartis and Tevaand serves on speakersrsquo bureaus for Biogen-Idec EMD-Serono Genentech Genzyme-Sanofi Novartis and Teva BSinger has received funding for travel andor speaker hon-oraria from Acorda Bayer Biogen EMD Serono Gen-entech Roche Novartis Sanofi Genzyme and Teva servesas a consultant for Bayer Biogen EMD Serono GenentechNovartis Sanofi Genzyme and Teva serves on speakersrsquobureaus for Acorda Bayer Biogen EMD Serono Gen-entech Novartis Sanofi Genzyme and Teva and receivesresearch support from Acorda Alkermes Biogen MedI-mmune Novartis Roche and Sanofi Genzyme V Singh isan employee of Fishawack Group of Companies whoseservices were paid for by Novartis A Boster serves asa consultant for Genzyme Genentech and Biogen serves onspeakersrsquo bureaus for Genzyme Genentech Biogen andNovartis and has received honoraria or research supportfrom Acorda Therapeutics Actelion Pharmaceuticals CNSTherapeutics Jazz Pharmaceuticals Medtronic RocheSerono Questcor Pharmaceuticals and Teva Pharmaceut-icals Full disclosure form information provided by theauthors is available with the full text of this article at Neu-rologyorgcp

TAKE-HOME POINTS

On the basis of the proposed MOAs of many of theDMTs used in the treatment of RMS lymphopenia isan anticipated side effect However not all patientsexperience lymphopenia and its severity may varybetween individuals

Lymphopenia is usually reversible after discontin-uation of most DMTs with infrequent exceptionsHowever the length of time for complete reversal oflymphopenia varies between individuals anddepends greatly on the specific DMT

Despite differences in MOAs of the various DMTsoverall rates of serious infection appear to be lowas reported in clinical trials

There is currently no direct evidence to suggest thatDMT efficacy in terms of either clinical response orbreakthrough MS activity is related to the presenceor severity of lymphopenia

The presence of lymphopenia following initiation ofDMTs known to cause cell lysis or redistribution isnot usually sufficient to warrant switching drugs orreducing dosage

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 1 | February 2019 61

Publication historyReceived by Neurology Clinical Practice October 6 2017 Accepted infinal form September 20 2018

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N Engl J Med 2000343938ndash9522 Tsang BK Macdonell R Multiple sclerosis- diagnosis management and prognosis

Aust Fam Physician 201140948ndash9553 Global Burden of Disease Study C Global regional and national incidence preva-

lence and years lived with disability for 301 acute and chronic diseases and injuries in188 countries 1990-2013 a systematic analysis for the Global Burden of DiseaseStudy 2013 Lancet 2015386743ndash800

4 Dilokthornsakul P Valuck RJ Nair KV Corboy JR Allen RR Campbell JD Multiplesclerosis prevalence in the United States commercially insured population Neurology2016861014ndash1021

5 Farjam M Zhang GX Ciric B Rostami A Emerging immunopharmacological targetsin multiple sclerosis J Neurol Sci 201535822ndash30

6 Blauth K Owens GP Bennett JL The ins and outs of B cells in multiple sclerosisFront Immunol 20156565

7 Blumenfeld S Staun-Ram E Miller A Fingolimod therapy modulates circu-lating B cell composition increases B regulatory subsets and production ofIL-10 and TGFbeta in patients with multiple sclerosis J Autoimmun 20167040ndash51

8 Bruck W Gold R Lund BT et al Therapeutic decisions in multiple sclerosis movingbeyond efficacy JAMA Neurol 2013701315ndash1324

9 GILENYAreg (Fingolimod) Prescribing Information 201610 AUBAGIOreg (Teriflunomide) Prescribing Information 201611 TECFIDERAreg (Dimethyl fumarate) Prescribing Information 201612 Trepel F Number and distribution of lymphocytes in man a critical analysis Klin

Wochenschr 197452511ndash51513 Westermann J Pabst R Lymphocyte subsets in the blood a diagnostic window on the

lymphoid system Immunol Today 199011406ndash41014 Winkelmann A Loebermann M Reisinger EC Hartung HP Zettl UK Disease-

modifying therapies and infectious risks in multiple sclerosis Nat Rev Neurol 201612217ndash233

15 Baker D Marta M Pryce G Giovannoni G Schmierer K Memory B cells are majortargets for effective immunotherapy in relapsing multiple sclerosis EBioMedicine20171641ndash50

16 Mehling M Fritz S Hafner P et al Preserved antigen-specific immune response inpatients with multiple sclerosis responding to IFNbeta-therapy PLoS One 20138e78532

17 Schwid SR Decker MD Lopez-Bresnahan M Rebif-Influenza Vaccine Study Inves-tigators Immune response to influenza vaccine is maintained in patients with multiplesclerosis receiving interferon beta-1a Neurology 2005651964ndash1966

18 Furlan R Bergami A Lang R et al Interferon-beta treatment in multiple sclerosispatients decreases the number of circulating T cells producing interferon-gamma andinterleukin-4 J Neuroimmunol 200011186ndash92

19 Boster AL Ford CC Neudorfer O Gilgun-Sherki Y Glatiramer acetate long-termsafety and efficacy in relapsing-remitting multiple sclerosis Expert Rev Neurother201515575ndash586

20 Messina S Patti F The pharmacokinetics of glatiramer acetate for multiple sclerosistreatment Expert Opin Drug Metab Toxicol 201391349ndash1359

21 Karandikar NJ Crawford MP Yan X et al Glatiramer acetate (Copaxone) therapyinduces CD8(+) T cell responses in patients with multiple sclerosis J Clin Invest2002109641ndash649

22 Winkelmann A LoebermannM Reisinger EC Zettl UK Multiple sclerosis treatmentand infectious issues update 2013 Clin Exp Immunol 2014175425ndash438

23 Olberg HK Cox RJ Nostbakken JK Aarseth JH Vedeler CA Myhr KM Immuno-therapies influence the influenza vaccination response in multiple sclerosis patientsan explorative study Mult Scler 2014201074ndash1080

24 Giovannoni G Kappos L Gold R et al Safety and tolerability profile of daclizumab inpatients with relapsing-remitting multiple sclerosis an integrated analysis of clinicalstudies Mult Scler Relat Disord 2016936ndash46

25 ZINBRYTAreg (Daclizumab) Prescribing Information 201626 Gold R Giovannoni G Selmaj K et al Daclizumab high-yield process in relapsing-

remitting multiple sclerosis (SELECT) a randomised double-blind placebo-controlled trial Lancet 20133812167ndash2175

27 Lebrun-Frenay C Rog D Benamor M Jurgensen S Truffinet P Ghezzi A Teri-flunomide (Aubagioreg) international pregnancy registry enrollment update Presentedat the 7th Joint ECTRIMS-ACTRIMS Meeting October 25ndash28 2017 Paris FrancePoster EP1732

28 Bar-Or A Pachner AMenguy-Vacheron F Kaplan J Wiendl H Teriflunomide and itsmechanism of action in multiple sclerosis Drugs 201474659ndash674

29 Bar-Or A Wiendl H Miller B et al Randomized study of teriflunomide effects onimmune responses to neoantigen and recall antigens Neurol Neuroimmunol Neu-roinflamm 20152e70

30 Berger JR Cree BA Greenberg B et al Progressive multifocal leukoencephalopathyafter fingolimod treatment Neurology 201890e1815ndashe1821

31 Rudnicka J Czerwiec M Grywalska E et al Influence of fingolimod onbasic lymphocyte subsets frequencies in the peripheral blood of multiple sclerosispatients - preliminary study Cent Eur J Immunol 201540354ndash359

32 Kappos L Mehling M Arroyo R et al Randomized trial of vaccination in fingolimod-treated patients with multiple sclerosis Neurology 201584872ndash879

33 Cohan SL Moses H Calkwood J et al Clinical outcomes in patients with relapsing-remitting multiple sclerosis who switch from natalizumab to delayed-release dimethyl

fumarate a multicenter retrospective observational study (STRATEGY) Mult SclerRelat Disord 20182227ndash34

34 Spencer CM Crabtree-Hartman EC Lehmann-Horn K Cree BA Zamvil SS Re-duction of CD8(+) T lymphocytes in multiple sclerosis patients treated with dimethylfumarate Neurol Neuroimmunol Neuroinflamm 20152e76

35 von Hehn C Howard L Liu S Meka V Pultz P Sheikh S A randomized open labelstudy to assess the immune response to vaccination in patients with relapsing forms ofmultiple sclerosis treated with delayedrelease dimethyl fumarate compared to non-pegylated interferon Presented at the 7th Joint ECTRIMS-ACTRIMS MeetingOctober 25ndash28 2017 Paris France Poster LB04

36 Longbrake EE Naismith RT Parks BJ Wu GF Cross AH Dimethyl fumarate-associated lymphopenia risk factors and clinical significance Mult Scler J Exp TranslClin 201511ndash8

37 Bomprezzi R Dimethyl fumarate in the treatment of relapsing-remitting multiplesclerosis an overview Ther Adv Neurol Disord 2015820ndash30

38 Singer BA The role of natalizumab in the treatment of multiple sclerosis benefits andrisks Ther Adv Neurol Disord 201710327ndash336

39 TYSABRIreg (Natalizumab) Prescribing Information 201640 Koudriavtseva T Sbardella E Trento E Bordignon V DrsquoAgosto G Cordiali-Fei

P Long-term follow-up of peripheral lymphocyte subsets in a cohort of multiplesclerosis patients treated with natalizumab Clin Exp Immunol 2014176320ndash326

41 Stuve O Marra CM Bar-Or A et al Altered CD4+CD8+ T-cell ratios in cerebro-spinal fluid of natalizumab-treated patients with multiple sclerosis Arch Neurol 2006631383ndash1387

42 Kaufman M Pardo G Rossman H Sweetser MT Forrestal F Duda P Natali-zumab treatment shows no clinically meaningful effects on immunizationresponses in patients with relapsing-remitting multiple sclerosis J Neurol Sci 201434122ndash27

43 Vagberg M Kumlin U Svenningsson A Humoral immune response to influenzavaccine in natalizumab-treated MS patients Neurol Res 201234730ndash733

44 Ziemssen T De Stefano N Pia Sormani M Van Wijmeersch B Wiendl H KieseierBC Optimizing therapy early in multiple sclerosis an evidence-based view Mult SclerRelat Disord 20154460ndash469

45 Zhang X Tao Y Chopra M et al Differential reconstitution of T cell subsetsfollowing immunodepleting treatment with alemtuzumab (anti-CD52 monoclonalantibody) in patients with relapsing-remitting multiple sclerosis J Immunol 20131915867ndash5874

46 LEMTRADAreg (Alemtuzumab) Prescribing Information 201447 McCarthy CL Tuohy O Compston DA Kumararatne DS Coles AJ Jones JL Im-

mune competence after alemtuzumab treatment of multiple sclerosis Neurology201381872ndash876

48 Hauser SL Bar-Or A Comi G et al Ocrelizumab versus interferon beta-1a in re-lapsing multiple sclerosis N Engl J Med 2017376221ndash234

49 OCREVUStrade (Ocrelizumab) Prescribing Information 201750 Hartung HP Arnold DL Bar-Or A et al Infections and serious infections with

ocrelizumab in relapsing multiple sclerosis and primary progressive multiple sclerosisMult Scler J 20162265876

51 Zafranskaya M Oschmann P Engel R et al Interferon-beta therapy reduces CD4+and CD8+ T-cell reactivity in multiple sclerosis Immunology 200712129ndash39

52 Rieckmann P OrsquoConnor P Francis GS Wetherill G Alteri E Haematological effectsof interferon-beta-1a (Rebif) therapy in multiple sclerosis Drug Saf 200427745ndash756

53 Lim ZW Elwood E Naveed H Galea I Lymphopenia in treatment-naive relapsingmultiple sclerosis Neurol Neuroimmunol Neuroinflamm 20163e275

54 Ireland SJ Guzman AA OrsquoBrien DE et al The effect of glatiramer acetate therapy onfunctional properties of B cells from patients with relapsing-remitting multiple scle-rosis JAMA Neurol 2014711421ndash1428

55 COPAXONEreg (Glatiramer Acetate Injection) Prescribing Information 201656 Brinkmann V Davis MD Heise CE et al The immune modulator FTY720 targets

sphingosine 1-phosphate receptors J Biol Chem 200227721453ndash2145757 Fox RJ Chan A Gold R et al Characterizing absolute lymphocyte count profiles in

dimethyl fumaratendashtreated patients with MS patient management considerationsNeurol Clin Pract 20166220ndash229

58 Zohren F Toutzaris D Klarner V Hartung HP Kieseier B Haas R The monoclonalanti-VLA-4 antibody natalizumab mobilizes CD34+ hematopoietic progenitor cells inhumans Blood 20081113893ndash3895

59 Thomas K Eisele J Rodriguez-Leal FA Hainke U Ziemssen T Acute effects ofalemtuzumab infusion in patients with active relapsing-remitting MS Neurol Neu-roimmunol Neuroinflamm 20163e228

60 AUBAGIOreg (Teriflunomide) Summary of Product Characteristics 201561 Berger JR Classifying PML risk with disease modifying therapies Mult Scler Relat

Disord 20171259ndash6362 Biogen AbbVie Press Release March 2 2018 [online] Available at businesswire

comnewshome20180302005168enBiogenC2A0and-AbbVie-AnnounceC2A0the-VoluntaryC2A0Worldwide-Withdrawal-Marketing-AuthorizationsAccessed March 29 2018

63 Mills EA Mao-Draayer Y Aging and lymphocyte changes by immunomodulatorytherapies impact PML risk in multiple sclerosis patients Mult Scler 2018241014ndash1022

64 Du Pasquier RA Kuroda MJ Zheng Y Jean-Jacques J Letvin NL Koralnik IJ Aprospective study demonstrates an association between JC virus-specific cytotoxicT lymphocytes and the early control of progressive multifocal leukoencephalopathyBrain 20041271970ndash1978

65 Ho PR Koendgen H Campbell N Haddock B Richman S Chang I Risk ofnatalizumab-associated progressive multifocal leukoencephalopathy in patients withmultiple sclerosis a retrospective analysis of data from four clinical studies LancetNeurol 201716925ndash933

62 Neurology Clinical Practice | Volume 9 Number 1 | February 2019 NeurologyorgCP

66 Buljevac D Flach HZ Hop WC et al Prospective study on the relationship betweeninfections and multiple sclerosis exacerbations Brain 2002125952ndash960

67 Warnke C Dehmel T Ramanujam R et al Initial lymphocyte count and low BMImayaffect fingolimod-induced lymphopenia Neurology 2014832153ndash2157

68 Bloomgren G Richman S Hotermans C et al Risk of natalizumab-associatedprogressive multifocal leukoencephalopathy N Engl J Med 20123661870ndash1880

69 Rae-Grant A Day GS Marrie RA et al Practice guideline recommendations sum-mary disease-modifying therapies for adults with multiple sclerosis report of theguideline development dissemination and implementation subcommittee of theAmerican Academy of Neurology Neurology 201890777ndash788

70 Fragoso YD Spelman T Boz C et al Lymphocyte count in peripheral blood is notassociated with the level of clinical response to treatment with fingolimod Mult SclerRelat Disord 201819105ndash108

71 Ruck T Bittner S Wiendl H Meuth SG Alemtuzumab in multiple sclerosis mech-anism of action and beyond Int J Mol Sci 20151616414ndash16439

72 Bodini B Calabresi PA From neurofilament research to multiple sclerosis clinicalpractice where do we stand Neurology 201788816ndash817

73 Zecca C Merlini A Disanto G et al Half-dose fingolimod for treating relapsing-remitting multiple sclerosis observational study Mult Scler 201824167ndash174

74 Klotz L Grutzke B Eveslage M et al Assessment of immune functions andMRI disease activity in relapsing-remitting multiple sclerosis patients switchingfrom natalizumab to fingolimod (ToFingo-Successor) BMC Neurol 20151596

75 Kappos L Radue EW OrsquoConnor P et al A placebo-controlled trial of oral fingolimodin relapsing multiple sclerosis N Engl J Med 2010362387ndash401

76 Calabresi PA Radue EW Goodin D Safety and efficacy of fingolimod inpatients with relapsing-remitting multiple sclerosis (FREEDOMS II) a double-blind randomised placebo-controlled phase 3 trial Lancet Neurol 201413545ndash556

77 Cohen JA Barkhof F Comi G et al Oral fingolimod or intramuscular interferon forrelapsing multiple sclerosis N Engl J Med 2010362402ndash415

78 Francis G Kappos L OrsquoConnor P et al Temporal profile of lymphocyte countsand relationship with infections with fingolimod therapy Mult Scler J 201420471ndash480

NeurologyorgCP Neurology Clinical Practice | Volume 9 Number 1 | February 2019 63

DOI 101212CPJ00000000000005672019953-63 Published Online before print January 8 2019Neurol Clin Pract

Edward J Fox Guy J Buckle Barry Singer et al neurologist

Lymphopenia and DMTs for relapsing forms of MS Considerations for the treating

This information is current as of January 8 2019

ServicesUpdated Information amp

httpcpneurologyorgcontent9153fullhtmlincluding high resolution figures can be found at

References httpcpneurologyorgcontent9153fullhtmlref-list-1

This article cites 66 articles 12 of which you can access for free at

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reserved Print ISSN 2163-0402 Online ISSN 2163-0933Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightssince 2011 it is now a bimonthly with 6 issues per year Copyright Copyright copy 2019 The Author(s)

is an official journal of the American Academy of Neurology Published continuouslyNeurol Clin Pract

BioVision Boston Scientific Dr Reddyrsquos electroCore EliLilly eNeura Therapeutics GlaxoSmithKline Merck PernixPfizer Supernus Teva Trigemina Vector and Vedanta Hereceives royalties fromWolffrsquos Headache 7th and 8th EditionOxford Press University 2009 Wiley and Informa Full dis-closure form information provided by the authors is availablewith the full text of this article at Neurologyorgcp

References1 Chelse AB Kurz JE Gorman KM et al Remote poststroke headache in children

Characteristics and association with stroke recurrence Neurol Clin Pract 20199194ndash200

2 Lai V Caplan L Are some ophthalmoplegias migrainous in origin Neurol Clin Pract20199256ndash262

3 Weissman B Joseph M Gronseth G Sarmiento K Giza CC CDCrsquos Guideline onPediatric Mild Traumatic Brain Injury Recommendations for neurologists NeurolClin Pract 20199241ndash249

4 Robblee J Kelly S Headache Illustrating the patient experience Neurol Clin Pract20199271ndash272

5 Goadsby P Primary headache disorders Five new things Neurol Clin Pract 20199233ndash240

6 Messina R Goadsby PJ CGRPmdasha target for acute therapy in migraine clinical dataCephalalgia 201939420ndash427

7 Edvinsson L Goadsby PJ Discovery of CGRP in relation to migraine Cephalalgia201939331ndash332

8 Turner S Foss-Barratt A Malmberg J Disabato J Minding the gap in pediatricheadache care Can a focus on quality measures improve outcomes Neurol Clin Pract20199187ndash193

CORRECTIONS

Message from the Editors to our Reviewers

Neurology Clinical Practice June 2019 vol 9 no 3 184 doi101212CPJ0000000000000677

In the article ldquoMessage from the Editors to our Reviewers by Corboy et al1 first published online April 8 2019 the penultimatesentence in Dr John Corboyrsquos disclosures should have read lsquoHe is a consultant to Novartis participating on a steeringcommittee and Mylan on a legal issuersquo The author regrets the error

Reference1 Corboy JR Powers LB Anderson DC and Barbano RL Message from the Editors to our Reviewers Neurol Clin Pract 2019990-92

Lymphopenia and DMTs for relapsing forms of MS Considerations for thetreating neurologist

Neurology Clinical Practice June 2019 vol 9 no 3 184 doi101212CPJ0000000000000676

In the infographic for the article ldquoLymphopenia and DMTs for relapsing forms of MS Considerations for the treatingneurologist by Fox et al1 first published online January 8 2019 a red ldquoXrdquo should have appeared on the arrow pointing toldquoegress into bloodstreamrdquo This was corrected online on February 11 2019 The authors regret the error

Reference1 Fox EJ Buckle GJ Singer B Singh V and Boster A Lymphopenia and DMTs for relapsing forms of MS Considerations for the treating neurologist Neurol Clin Pract 2019953-63

184 Neurology Clinical Practice | Volume 9 Number 3 | June 2019 NeurologyorgCP

Copyright copy 2019 American Academy of Neurology Unauthorized reproduction of this article is prohibited