ARTHRITIS & RHEUMATISMVol. 54, No. 5, May 2006, pp 1429–1434DOI 10.1002/art.21814© 2006, American College of Rheumatology

Guillain-Barre and Miller Fisher Syndromes Occurring WithTumor Necrosis Factor � Antagonist Therapy

In-Sook J. Shin,1 Alan N. Baer,1 Hyon J. Kwon,2 Elektra J. Papadopoulos,2

and Jeffrey N. Siegel2

Objective. Diverse neurologic syndromes havebeen described in association with tumor necrosis factor� (TNF�) antagonist therapy for inflammatory arthrit-ides and Crohn’s disease. The objective of this study wasto review the occurrence and clinical features ofGuillain-Barre syndrome and its variant, the MillerFisher syndrome, during TNF� antagonist therapy.

Methods. The postmarketing database of the USFood and Drug Administration (FDA) was searched,following our experience with a patient with rheumatoidarthritis in whom the Miller Fisher syndrome variant ofthe Guillain-Barre syndrome developed while he wasreceiving infliximab therapy.

Results. Our index patient had a neurologic ill-ness defined initially by ataxia and dysarthria, whichfluctuated in relation to each subsequent infliximabinfusion and, after 6 months, culminated in areflexicflaccid quadriplegia. In addition, 15 patients in whomGuillain-Barre syndrome developed following TNF�antagonist therapy were identified from the FDA data-base. Guillain-Barre syndrome developed following in-fliximab therapy in 9 patients, following etanercepttherapy in 5 patients, and following adalimumab ther-apy in 1 patient. Among the 13 patients for whomfollowup data were available, 1 patient experienced noresolution, 9 patients had partial resolution, and 3patients had complete resolution of Guillain-Barre syn-drome following therapy.

Conclusion. An association of Guillain-Barre syn-drome with TNF� antagonist therapy is supported bythe worsening of neurologic symptoms that occurred inour index patient following each infusion of infliximab,and by the temporal association of this syndrome withTNF� antagonist therapy in 15 other patients. An acuteor subacute demyelinating polyneuropathy should beconsidered a potential adverse effect of TNF� antago-nist therapy.

Tumor necrosis factor � (TNF�) antagonist ther-apy for inflammatory arthritides and Crohn’s disease hasbeen associated with the development of demyelinationin the central nervous system and the peripheral nervoussystem (1,2). The demyelination has been characterizedclinically as multiple sclerosis, optic neuritis, transversemyelitis, Guillain-Barre syndrome, or chronic inflamma-tory demyelinating polyneuropathy (CIDP). One case ofGuillain-Barre syndrome occurred during clinical trialsof infliximab. Following the marketing of infliximab, 9cases of Guillain-Barre syndrome or CIDP were re-ported to the manufacturer (2). Two additional cases ofCIDP occurring in association with TNF� antagonisttherapy have now been reported (3).

We now report a patient with rheumatoid arthri-tis in whom ataxia and dysarthria developed while he wasreceiving infliximab therapy; his neurologic syndromeworsened with successive infusions of infliximab and,after 6 months, culminated as the Miller Fisher syn-drome variant of the Guillain-Barre syndrome. In addi-tion, we describe 15 other patients identified from thepostmarketing database of the US Food and DrugAdministration (FDA) in whom Guillain-Barre syn-drome developed while they were receiving TNF� an-tagonist therapy.

PATIENTS AND METHODSDatabase search. The FDA’s Adverse Event Report-

ing System (AERS) database contains postmarketing reports

Presented in part at the 57th Annual Meeting of the Ameri-can Academy of Neurology, Miami, FL, April 12, 2005.

1In-Sook J. Shin, MD, Alan N. Baer, MD: State University ofNew York at Buffalo; 2Hyon J. Kwon, PharmD, MPH, Elektra J.Papadopoulos, MD, Jeffrey N. Siegel, MD: Center for Drug Evalua-tion and Research, FDA, Silver Spring, Maryland.

Drs. Shin and Baer contributed equally to this work.Address correspondence and reprint requests to Alan N.

Baer, MD, Erie County Medical Center, 462 Grider Street, Buffalo,NY 14215. E-mail: alanbaer@buffalo.edu.

Submitted for publication September 9, 2005; accepted inrevised form February 6, 2006.

1429

of adverse events related to FDA-approved medications. InSeptember 2004, we performed a search of the AERS databasefor reports of Guillain-Barre syndrome or Miller Fisher syn-drome in patients receiving infliximab (Remicade), etanercept(Enbrel), or adalimumab (Humira), using the preferred terms“Guillain-Barre syndrome” and “Miller Fisher syndrome”from the Medical Dictionary for Regulatory Activities. Pa-tients who were included were those in whom Guillain-Barresyndrome or Miller Fisher syndrome was diagnosed in tempo-ral association with TNF� antagonist therapy. A medicalliterature search in PubMed yielded 1 case report of Guillain-Barre syndrome occurring in association with infliximab ther-apy (4). This case was in the AERS database and is included inthe current report. A second patient with Guillain-Barresyndrome was included in a previous report of demyelinationoccurring in patients receiving TNF� antagonist therapy (1).

Index patient. A 56-year-old man with seropositiverheumatoid arthritis began therapy with infliximab 21 monthsprior to hospital admission. He responded well to therapy,which allowed a decrease in the dosage of previously pre-scribed methotrexate and discontinuation of sulfasalazine.Twenty-four weeks prior to hospital admission, the patientbecame unsteady while walking. This ataxia developed 6 weeksafter his most recent infliximab infusion and 6 days followingthe administration of influenza vaccine. His ataxia graduallyimproved, but dysarthria and worsening ataxia developed�3–4 weeks after each subsequent infusion (Figure 1). Thelatter symptom progressed transiently to the point at which hewas unable to ambulate for 2 weeks.

Fourteen weeks prior to hospital admission, the pa-tient experienced a widespread and persistent eczematous rashwith recurrence of ataxia. His ataxia and dysarthria worsened

again, following an infliximab infusion that was administered 3weeks prior to hospital admission. Physical examination at thetime of hospital admission revealed dysarthric speech, horizon-tal nystagmus, marked truncal and appendicular dystaxia, andhyperreflexia with withdrawal plantar reflexes. Eczematousskin lesions were present on his lower extremities and torso.The patient’s diagnostic evaluation is shown in Table 1.

One week after he was admitted to the hospital, thepatient’s mental status fluctuated, from lethargic to obtunded.By the ninth hospital day, he had a partial right abductor palsy,generalized weakness, and diffuse hyporeflexia. Intravenousmethylprednisolone (1,000 mg) was given daily for 2 days,resulting in transient improvement in the patient’s mentalstatus. However, his weakness progressed, leading to pareticdysarthria, poor swallowing, and virtually absent deep tendonreflexes.

Following electrodiagnostic testing, a diagnosis ofMiller Fisher syndrome was established. Subsequently, thepatient received a 5-day course of intravenous immunoglobulin(IVIG), 0.4 gm/kg/day. His neurologic condition deterioratedfurther, with development of areflexic flaccid quadriplegia,bifacial and bulbar palsies, and fluctuating mental status. Thepatient showed rapid improvement after receiving a secondcourse of IVIG therapy. Two months later, he was able to walkwith the aid of parallel bars, and at 6 months he was ambulat-ing without use of an assistive device. Seventeen months afterhospitalization, double-stranded DNA and RNP autoantibod-ies were no longer detectable.

RESULTS

We identified 15 patients in the FDA’s postmar-keting database in whom Guillain-Barre syndrome de-veloped following TNF� antagonist therapy. Nine ofthese patients had received infliximab, 5 had receivedetanercept, and 1 patient had received adalimumab.Supporting clinical and/or diagnostic information wasnot provided for 2 of these 15 patients. Clinical summa-ries for the remaining 13 patients and the index patientare provided in Table 2. The median age of these 14patients was 56 years (range 34–81 years). The medianinterval from the first administration of TNF� antago-nist therapy to the onset of Guillain-Barre syndrome was4 months (range 1.5 months to 2 years; n � 11 patients).Electrodiagnostic findings that supported the diagnosisof Guillain-Barre syndrome were reported in 9 patients.In 6 patients, antecedent events included upper respira-tory tract infection, flu-like illness, or low-grade fever,and in 1 patient the antecedent event was a fever ofunknown origin. Thirteen patients received therapy forGuillain-Barre syndrome, which included plasmaphere-sis, IVIG, and/or corticosteroids.

Nine patients experienced partial resolution, and3 patients had complete resolution of Guillain-Barresyndrome. One patient continued to have symptoms,

Figure 1. Correlation between clinical course and infliximab infusionsin the index patient, showing the temporal relationship between theinfliximab infusions and the severity of his neurologic illness. Theseverity of the patient’s neurologic symptoms was graded using theExpanded Disability Status Scale (EDDS) (16). For this patient, grade2 corresponded to mild ataxia, grade 4 corresponded to moderateataxia but ambulating with aid, grade 6 corresponded to dysarthria andinability to ambulate without assistance due to severe ataxia, and grade9.5 corresponded to quadriplegia with inability to swallow or commu-nicate. IVIG � intravenous immunoglobulin.

1430 SHIN ET AL

and the outcome of the remaining 3 patients is unknown.Two patients who experienced partial resolution had arelapsing course, in which the neurologic symptomsimproved and then recurred without further exposure toa TNF� antagonist. In the index patient, ataxia im-proved but recurred along with worsening neurologicsymptoms upon further exposure to infliximab (positiverechallenge). Another patient had a positive rechal-lenge, in which her acute neuromuscular weakness re-curred following a subsequent infliximab infusion. How-ever, 2 patients experienced no recurrence of Guillain-Barre syndrome when TNF� antagonist therapy wasreinitiated several months after the event (negativerechallenge); in 1 of these patients the rechallengeinvolved a lower dose of infliximab.

DISCUSSION

We report 16 patients in whom Guillain-Barresyndrome developed in association with TNF� antago-nist therapy. These cases of Guillain-Barre syndromemay have occurred as a consequence of this biologic

therapy or as a consequence of an unrelated triggeringevent, such as an antecedent infection. However, posi-tive temporal relationships with TNF� antagonist ther-apy in all of the patients support the first possibility. Sixpatients had a preceding upper respiratory tract infec-tion, flu-like illness, or low-grade fever, and the indexpatient had received influenza vaccine 6 days before theonset of ataxia. Nevertheless, the role of TNF� antago-nist therapy could not be excluded, despite the presenceof antecedent events that possibly triggered Guillain-Barre syndrome in several patients.

Guillain-Barre syndrome is the most frequentcause of acute or subacute flaccid paralysis. The clinicalcourse of this inflammatory polyradiculoneuropathy istypically monophasic. Guillain-Barre syndrome com-prises a heterogeneous group of conditions defined byvarying clinical, electrophysiologic, and pathologic fea-tures (5). One variant is the Miller Fisher syndrome,which comprises �3–5% of Guillain-Barre syndromecases in Western countries and is characterized by thetriad of ataxia, external ophthalmoplegia, and areflexia.

Table 1. Laboratory findings in the index patient*

Test Result

Cerebrospinalfluid analyses

1st hospital day: 121 NBC (95% lymphocytes), protein 67 mg/dl, glucose54 mg/dl, IgG 10.7 mg/dl.

19th hospital day: 36 NBC, protein 79 mg/dl.35th hospital day: 0 NBC, protein 57 mg/dl.Negative for herpes simplex virus, varicella-zoster virus, cytomegalovirus,

Epstein-Barr virus, enterovirus, and arboviruses, by polymerase chainreaction.

Serologic tests GQ1b IgG antibody titer �1:100; HIV negative;Lyme antibody negative; rheumatoid factor 68 IU/ml; ANA titer 1:640,homogeneous (ANA negative at diagnosis 2 years earlier); dsDNA anti-body titer 1:20 (Crithidia luciliae assay); RNP antibody positive.

Electromyography/nerve conduction

12th day: absent F-wave responses from both median and the right ulnarnerves and prolongation of the F wave response from the left peronealnerve (indicative of a proximal conduction block).

28th day: absence of F waves in 6 motor nerves and no electrical responsefrom the peroneal, superficial peroneal, sural, and left ulnar nerves.

Magnetic resonanceimaging

Brain: age-related microvascular white matter changes (31 days prior tohospital admission and on 3rd, 10th, and 21st hospital days).Cervical, thoracic, and lumbar spines: normal.

Cerebral angiography Normal.

Electroencephalography Normal.

Skin biopsy Subacute spongiotic dermatitis with intraepithelial microabscesses anddermal perivascular mononuclear cell infiltrate with scatteredneutrophils and eosinophils.

* NBC � nucleated blood cell; HIV � human immunodeficiency virus; ANA � antinuclear antibody;dsDNA � double-stranded DNA.

GUILLAIN-BARRE SYNDROME AND TNF� ANTAGONIST THERAPY 1431

Tab

le2.

Cha

ract

eris

tics

ofG

uilla

in-B

arre

synd

rom

eoc

curr

ing

with

TN

F�

anta

goni

stth

erap

y*

Age

/sex

Indi

catio

n

Dru

g/du

ratio

nof

ther

apy/

no.o

fin

fusi

ons

Clin

ical

sign

san

dsy

mpt

oms

Ant

eced

ent

even

tsE

MG

/NC

The

rapy

Out

com

e

56/M

†R

AIn

flixi

mab

/15

mon

ths/

12A

taxi

a,dy

sart

hria

prog

ress

ing

toar

efle

xic

quad

ripl

egia

Flu

vacc

ine

Dem

yelin

atin

gpo

lyne

urop

athy

with

prox

imal

cond

uctio

nde

fect

IVIG

,m

ethy

lpre

dnis

olon

ePa

rtia

lres

olut

ion

at3.

5m

onth

s;po

sitiv

ere

chal

leng

ew

ithsu

bseq

uent

3in

fusi

ons

49/F

Cro

hn’s

dise

ase

Infli

xim

ab/

seve

ral

year

s/2

Wea

knes

s,re

spir

ator

ydi

stre

ssL

ow-g

rade

feve

rof

shor

tdu

ratio

n

Acu

tede

mye

linat

ing

poly

neur

opat

hy

IVIG

Not

repo

rted

66/F

RA

Infli

xim

ab/8

mon

ths/

6Pr

ogre

ssiv

ew

eakn

ess

and

imba

lanc

eN

otre

port

edIV

IGN

ore

spon

seto

ther

apy

56/F

RA

Infli

xim

ab/6

mon

ths/

4Sy

mm

etri

cqu

adri

pare

sis

UR

IA

xona

lpo

lyne

urop

athy

IVIG

Part

ialr

esol

utio

nat

2w

eeks

43/M

Psor

iatic

arth

ritis

Infli

xim

ab/5

mon

ths/

5A

scen

ding

prog

ress

ive

quad

ripa

resi

s,ur

inar

yre

tent

ion

Acu

tede

mye

linat

ing

poly

neur

opat

hy

Not

repo

rted

Part

ialr

esol

utio

nat

2w

eeks

62/M

RA

Infli

xim

ab/3

–4m

onth

s/4

Prog

ress

ive

asce

ndin

gpa

raly

sis,

pare

sthe

sia

ofle

gs,i

nabi

lity

tow

alk

Feve

rof

unkn

own

orig

in

Not

repo

rted

IVIG

,pl

asm

aphe

resi

s,m

echa

nica

lve

ntila

tion

Part

ialr

esol

utio

nat

10m

onth

s

34/M

‡Ps

oria

ticar

thri

tisIn

flixi

mab

/3.5

mon

ths/

2A

scen

ding

para

lysi

sU

RI;

MFS

14ye

ars

earl

ier

Dem

yelin

atin

gpo

lyra

dicu

lo-

neur

opat

hy

Mec

hani

cal

vent

ilatio

n,IV

IGC

ompl

ete

reso

lutio

nat

3w

eeks

;neg

ativ

ere

chal

leng

eat

1m

onth

81/F

RA

Infli

xim

ab/

not

repo

rted

/4W

eakn

ess,

pare

sthe

sia,

decr

ease

ddi

aphr

agm

atic

func

tion

Nor

mal

at1

wee

kIV

IG,

plas

map

here

sis

Rel

apse

off-

drug

;pa

rtia

lres

olut

ion

41/F

Cro

hn’s

dise

ase

Infli

xim

ab/

not

repo

rted

/2A

cute

neur

omus

cula

rw

eakn

ess;

pree

xist

ing

myo

toni

cdy

stro

phy

Dem

yelin

atin

gpo

lyne

urop

athy

Not

repo

rted

Part

ialr

esol

utio

n;po

sitiv

ere

chal

leng

eaf

ter

each

infu

sion

58/F

RA

Eta

nerc

ept/

2ye

ars

Prog

ress

ive

asce

ndin

gpa

raly

sis,

pare

sthe

sia

ofar

ms

and

face

Flu-

like

illne

ssN

otre

port

edIV

IG,

ster

oid

Mul

tiple

rela

pses

over

6m

onth

sof

f-dr

ug;p

artia

lres

olut

ion

at�

9m

onth

s58

/FR

AE

tane

rcep

t/4

mon

ths

Prog

ress

ive

wea

knes

san

ddi

ffic

ulty

ambu

latin

g

Dem

yelin

atin

gpo

lyne

urop

athy

IVIG

Com

plet

ere

solu

tion

at6

wee

ks

53/M

§R

AE

tane

rcep

t/2.

5m

onth

sPr

ogre

ssiv

equ

adri

pare

sis,

pare

sthe

sia

Poly

radi

culo

-ne

urop

athy

Plas

map

here

sis

Part

ialr

esol

utio

nat

1w

eek

36/F

RA

Eta

nerc

ept/

not

repo

rted

Pare

sthe

sia

ofup

per

and

low

erex

trem

ities

UR

IN

otre

port

edIV

IGC

ompl

ete

reso

lutio

n;ne

gativ

ere

chal

leng

eat

3m

onth

s61

/FR

AA

dalim

umab

/1.

5m

onth

sPr

ogre

ssiv

equ

adri

pare

sis,

hypo

refle

xia,

hypo

esth

esia

info

ot

Flu-

like

illne

ssA

xona

lmot

or-

sens

ory

poly

neur

opat

hy

IVIG

Part

ialr

esol

utio

nat

1m

onth

*T

NF

��

tum

orne

cros

isfa

ctor

�;E

MG

/NC

�el

ectr

omyo

gram

/ner

veco

nduc

tion;

RA

�rh

eum

atoi

dar

thri

tis;I

VIG

�in

trav

enou

sim

mun

oglo

bulin

;UR

I�

uppe

rre

spir

ator

ytr

act

infe

ctio

n;M

FS

�M

iller

Fis

her

synd

rom

e.†

Inde

xca

se.

‡L

itera

ture

case

(4).

§L

itera

ture

case

(1).

1432 SHIN ET AL

Antibodies to ganglioside GQ1b are detected in 80–90%of patients.

The index patient presented with cerebellarataxia and nystagmus and ultimately experienced anareflexic flaccid quadriplegia and bifacial and bulbarpalsies. This sequence of clinical events is consistent withprogression of the Miller Fisher syndrome to a general-ized form of Guillain-Barre syndrome. Several featuresof the index patient’s Guillain-Barre syndrome point toinduction of the syndrome by infliximab; these featuresinclude the temporal association of disease developmentwith infliximab therapy, the unusually protracted pro-drome, and the coincidental development of a skin rash(which was considered to be drug-related) and lupus-related autoantibodies. Finally, the index patient im-proved dramatically over 2 months after discontinuationof infliximab and treatment with IVIG. The prognosis ofGuillain-Barre syndrome is highly dependent on thelevel of disease severity, and recovery may continue forup to 2 years in patients who are affected as severely aswas the index patient (6).

It would be desirable to assess outcomes andresolution rates in each of the patients in this series.Unfortunately, only limited information is available insome of the reports. The outcome of 3 patients andcomplete information about the severity of the Guillain-Barre syndrome in many of the reported patients werenot provided. Accordingly, we cannot compare the res-olution rates among the postmarketing cases with thosein other Guillain-Barre syndrome cohorts.

Guillain-Barre syndrome was temporally associ-ated with infliximab therapy in 10 patients and withetanercept therapy in 5 patients; except for 1 caseinvolving infliximab, all of the cases occurred in the US.The only case reported in association with adalimumabcame from outside the US. In the US, �303,000 patientshave received infliximab from the time of its approval inAugust 1998 to August 2004 (Centocor: unpublisheddata). An estimated total of 280,000 patients in the USreceived etanercept from the time of its approval inNovember 1998 to January 2005 (Amgen: unpublisheddata). This compares with an annual incidence ofGuillain-Barre syndrome of 1–3/100,000 population (7).However, these data should be interpreted cautiously,because significant underreporting is known to occur ina postmarketing surveillance system. An examination oflarge epidemiologic databases will be necessary to de-termine the true incidence of drug-related adverseevents.

Guillain-Barre syndrome is thought to arise from

an aberrant immune response to peripheral nerve mye-lin or axons, triggered by an antecedent event such asinfection. Such infections are reported by two-thirds ofpatients with Guillain-Barre syndrome, and the etiologicagents include Campylobacter jejuni, cytomegalovirus,Epstein-Barr virus, varicella-zoster virus, Hemophilusinfluenzae, and Mycoplasma pneumoniae (7). In epide-miologic studies, the risk of developing Guillain-Barresyndrome following influenza vaccination is reported tobe slightly increased (8). In such cases, epitopes sharedbetween the infectious organism and nerve fibers arethought to be targets for an aberrant cross-reactiveimmune response (molecular mimicry) (9). Susceptibil-ity to the development of Guillain-Barre syndrome islikely dependent on subsequent events, influenced inpart by the immunogenetic background of the host.

Synergy between cellular and humoral immuneresponses to unknown peripheral nerve antigens hasbeen postulated to underlie the immunopathogenesis ofGuillain-Barre syndrome. High levels of markers of Tcell activation have been demonstrated in the serum ofpatients with Guillain-Barre syndrome (10). TNF� andother cytokines have been implicated in the pathogene-sis of Guillain-Barre syndrome. Levels of TNF� areelevated in the serum of affected patients, correlate (inmany studies) with disease severity, and normalize inparallel with the clinical recovery of patients (11). Theseobservations support a proinflammatory function ofTNF� in Guillain-Barre syndrome.

TNF� has also been shown to have immunoregu-latory functions. It suppresses T cell reactivity to autoan-tigens in animal models of autoimmunity (12). TNF�deficiency leads to failed regression of myelin-specific Tcell reactivity and prolonged survival of activated T cells(13). When endogenous TNF� is blocked by repeatedinjections of a TNF� antagonist, T cell proliferativeresponses and cytokine production are enhanced (12).The prolonged administration of TNF� antagonists isthought to enhance autoimmune responses by potenti-ating T cell receptor signaling and decreasing apoptosisof autoreactive T cells (14). A systemically administeredTNF� antagonist potentially could enter the peripheralnervous system at the roots and motor nerve terminals,where the blood–nerve barrier is absent or relativelydeficient. If this occurs, TNF� within the peripheralnervous system compartment is neutralized or reduced.Too little TNF� may augment or prolong the myelin-specific T cell response and increase the risk of developingor prolonging an immune-mediated neuropathy (15).

TNF� antagonist therapy could promote the de-velopment of Guillain-Barre syndrome by augmenting

GUILLAIN-BARRE SYNDROME AND TNF� ANTAGONIST THERAPY 1433

the number of activated peripheral T cells or by disturb-ing the intrinsic balance of TNF� and its receptors in thelocal peripheral nervous system compartment. Thesefactors, alone or in combination, could induce theclinical expression of Guillain-Barre syndrome in immu-nogenetically susceptible patients. Guillain-Barre syn-drome is typically a self-limited, monophasic disease.Our index patient had been receiving TNF� antagonisttherapy for 15 months before the initial development ofneurologic symptoms. Each episode of these symptomswas similar but recurred, on average, 3.5 weeks followingthe subsequent 3 infusions of infliximab. His neurologicsymptoms increased with cumulative exposure to thebiologic agent, and the flares that occurred after eachinfliximab infusion were longer and more severe. Aprolonged and intensified pathogenic autoimmune re-sponse, induced by TNF� antagonist therapy, couldexplain the patient’s symptom flares that occurred fol-lowing each infliximab infusion. Two of the other pa-tients reported here had unusual relapsing courses. Wepostulate that the duration and the extent of exposure toa TNF� antagonist may permit development of anatypical autoimmune response once the disease is in-duced.

The safety of TNF� antagonist therapy is acrucial issue, because use of such therapy is increasingevery year, particularly following its approval for addi-tional indications. In this report, we summarized a seriesof patients in whom Guillain-Barre syndrome developedin association with TNF� antagonist therapy. Although acausal relationship between Guillain-Barre syndromeand TNF� antagonist therapy cannot be proven, clini-cians should monitor patients who are receiving TNF�antagonist therapy for neurologic signs and symptomssuggestive of demyelinating disease in either the centralor peripheral nervous system.

ACKNOWLEDGMENTS

We gratefully acknowledge the roles of Drs. MaryAnnMays (Cleveland Clinic Foundation) and Prem Tambar (Ni-agara Falls, NY) in the clinical care of this patient. We thankMs Roberta Sullivan for technical assistance with the figure.

REFERENCES

1. Mohan N, Edwards ET, Cupps TR, Oliverio PJ, Sandberg G,Crayton H, et al. Demyelination occurring during anti–tumornecrosis factor � therapy for inflammatory arthritides. ArthritisRheum 2001;44:2862–9.

2. US Food and Drug Administration. Arthritis Advisory CommitteeBriefing Document. URL: http://www.fda.gov/ohrms/dockets/ac/03/briefing/3930B1_04_A-Centocor-Remicade%20.pdf.

3. Richez C, Blanco P, Lagueny A, Schaeverbeke T, Dehais J. Neu-ropathy resembling CIDP in patients receiving tumor necrosisfactor-� blockers. Neurology 2005;6:1468–70.

4. Cisternas M, Gutierrez M, Jacobelli S. Successful rechallenge withanti–tumor necrosis factor � for psoriatic arthritis after develop-ment of demyelinating nervous system disease during initial treat-ment: comment on the article by Mohan et al [letter]. ArthritisRheum 2002;46:3107–8.

5. Hughes RA. The concept and classification of Guillain-Barresyndrome and related disorders. Rev Neurol (Paris) 1995;151:291–4.

6. The Italian Guillain-Barre Study Group. The prognosis and mainprognostic indicators of Guillain-Barre syndrome: a multicentreprospective study of 297 patients. Brain 1996;119:2053–61.

7. Hahn AF. Guillain-Barre syndrome. Lancet 1998;352:635–41.8. Lasky T, Terracciano GJ, Magder L, Koski CL, Ballesteros M,

Nash D, et al. The Guillain-Barre syndrome and the 1992-1993and 1993-1994 influenza vaccines. N Engl J Med 1998;339:1797–802.

9. O’Leary CP, Willison HJ. The role of antiglycolipid antibodies inperipheral neuropathies. Curr Opin Neurol 2000;13:583–8.

10. Hartung HP, Hughes RA, Taylor WA, Heininger K, Reiners K,Toyka KV. T cell activation in Guillain-Barre syndrome and inMS: elevated serum levels of soluble IL-2 receptors. Neurology1990;40:215–8.

11. Sharief MK, McLean B, Thompson EJ. Elevated serum levels oftumor necrosis factor-� in Guillain-Barre syndrome. Ann Neurol1993;33:591–6.

12. Cope A, Ettinger R, McDevitt H. The role of TNF � and relatedcytokines in the development and function of the autoreactiveT-cell repertoire. Res Immunol 1997;148:307–12.

13. Kassiotis G, Kollias G. Uncoupling the proinflammatory from theimmunosuppressive properties of tumor necrosis factor (TNF) atthe p55 TNF receptor level: implications for pathogenesis andtherapy of autoimmune demyelination. J Exp Med 2001;193:427–34.

14. Cope AP, Liblau RS, Yang XD, Congia M, Laudanna C, SchreiberRD, et al. Chronic tumor necrosis factor alters T cell responses byattenuating T cell receptor signaling. J Exp Med 1997;185:1573–84.

15. Tsang RS, Valdivieso-Garcia A. Pathogenesis of Guillain-Barresyndrome. Expert Rev Anti Infect Ther 2003;1:597–608.

16. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: anexpanded disability status scale (EDSS). Neurology 1983;33:1444–52.

1434 SHIN ET AL