r e v b r a s r e u m a t o l . 2017;57(6):590–595
ww w . r e u m a t o l o g i a . c o m . b r
REVISTA
BRASILEIRA
DE
REUMATOLOGIA
Review
article
Three
cases
of
anti-TNF
induced
myositis
and
literature
review
Orhan
Zengin
a,∗,
Mustafa
Erkut
Onder
a,
Samet
Alkan
b,
Gezmis¸
Kimyon
a,
Nergis
Hüseynova
a,
Zeynep
Hanım
Demir
c,
Bünyamin
Kısacık
a,
Ahmet
Mesut
Onat
aaGaziantepUniversity,SchoolofMedicine,DepartmentofRheumatology,Gaziantep,Turkey bGaziantepUniversity,SchoolofMedicine,DepartmentofInternalMedicine,Gaziantep,Turkey cNYUSchoolofMedicine,CenterforCognitiveNeurology,NewYork,UnitedStates
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received20August2015
Accepted8December2015
Availableonline1June2016
Keywords:
Anti-tumornecrosisfactor
(anti-TNF)drugs
Myositis Jo-1
a
b
s
t
r
a
c
t
Anti-tumornecrosisfactordrugsarefrequentlypreferredinthetreatmentofrheumatologic
diseasesandotherinflammatorydiseases.Thedevelopmentofmyositisafterusing
anti-tumornecrosisfactordrugsisarareclinicalcondition.Hereweaimedtoreportcaseswho
developedmyositisafterusinganti-tumornecrosisfactordrugsandreviewthecurrent
literature.Wereporttwocasesofrheumatoidarthritisandacaseofankylosingspondylitis
developedidiopathicinflammatorymyopathyfollowinganti-tumornecrosisfactortherapy.
Inconclusion,myositiscoulddevelopduringanti-tumornecrosisfactortherapy,sothese
patientsshouldbeevaluatedcarefullyinitiallyformyositisandshouldbecloselymonitored
duetothepotentialfordevelopingmyositisintreatmentprocess.
©2016ElsevierEditoraLtda.ThisisanopenaccessarticleundertheCCBY-NC-ND
license(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Três
casos
de
miosite
induzida
pelo
anti-TNF
e
revisão
da
literatura
Palavras-chave:
Fármacosantifatordenecrose
tumoral(anti-TNF)
Miosite Jo-1
r
e
s
u
m
o
Osfármacosantifatordenecrosetumoral(anti-TNF)sãofrequentementepreferidosno
tratamentodedoenc¸asreumatológicaseoutrasdoenc¸asinflamatórias.Odesenvolvimento
demiositeapósousodeanti-FNTéumacondic¸ãoclínicarara.Esteestudoobjetivou
descr-evercasosdepacientesquedesenvolverammiositeapósousodeanti-TNFefazeruma
revisãodaliteraturaatual.Descrevem-sedoiscasosdeartritereumatoide(AR)eumcasode
espondiliteanquilosante(EA)quedesenvolverammiopatiainflamatóriaidiopáticaapóso
tratamentocomanti-TNF.Emconclusão,podehaverdesenvolvimentodemiositeduranteo
tratamentocomanti-TNF,demodoqueessespacientesdevemsercuidadosamente
avalia-dosinicialmenteàprocurademiositeedevemsercuidadosamentemonitoradosemrazão
dopotencialdedesenvolvimentodemiositenoprocessodetratamento.
©2016ElsevierEditoraLtda.Este ´eumartigoOpenAccesssobumalicenc¸aCC
BY-NC-ND(http://creativecommons.org/licenses/by-nc-nd/4.0/).
∗ Correspondingauthor.
E-mail:drorhanzengin@gmail.com(O.Zengin).
http://dx.doi.org/10.1016/j.rbre.2016.05.003
2255-5021/©2016ElsevierEditoraLtda.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/
Introduction
Tumor necrosis factor alpha (TNF-␣) is a proinflammatory
cytokine that plays animportant role inthe pathogenesis
ofRA, AS and many other inflammatory diseases. Due to
itsroleintheinflammatoryprocess,anti-TNFdrugsare
fre-quentlypreferredinthetreatmentofrheumatologicdiseases
andotherinflammatorydiseases.1
Although anti-TNF drugs generally demonstrate their
anti-inflammatoryeffectsbyantagonizingTNF-␣,theyhave
differenteffects on the immunesystem and inflammation
depending on their chemical structures and physiological
characteristics.This different efficacy determines both the
clinical indications and side effect profile of the drugs.
The main side effects of the drugs are predisposition to
infections, allergic reactions, malignancies, demyelinating
diseases,congestiveheartfailure, bonemarrowdepression,
and autoimmune diseases.2 The development of myositis
afterusinganti-TNFisarareclinicalcondition.3Weaimed
topresentthreecasesfollowedupwiththediagnosisofAS
andRAwhichdevelopedmyositisafterusinganti-TNF.
Case
1
A30-year-old male patient had been followed-up withthe
diagnosisofASfortenyears.Hehadbeentakingnon-steroidal
anti-inflammatory drugs (NSAID) for 10 years. Etanercept
25mg2times aweekwasinitiatedashiscomplaintshave
increased.Thepatienthad takenatotalof20 (2.5months)
dosesofetanercepttreatmentandthepatienthadcomplaints
of weakness, fatigue and difficulty in climbing the stairs
withinthelastthreeweeks.Uponhisphysicalexamination
therewasweaknessinproximalmusclesofupperandlower
extremities,yet nodermatological involvementwasfound.
Aspartateaminotransferase(AST),alanineaminotransferase
(ALT),creatininekinase(CK)andlactatedehydrogenase(LDH)
were536U/L,535U/L,6035U/L,and739U/L,respectively.
Thy-roidstimulatinghormone(TSH)andotherbiochemicaltests
were normal. ANA was 1/160 positive, anti Jo-1 was
pos-itive, and anti dsDNA, anti-SSA, anti-RNP were negative.
Electromyography(EMG)findingsrevealedmyopathyin
prox-imal muscles. The deltoid muscle biopsy was consistent
with polymyositis. Etanercept was stopped and three-day
pulsesteroid(1g)treatmentwasstartedwiththediagnosis
ofinflammatorymyositis, and subsequently 1g
cyclophos-phamide/month treatmentwas started. Atthe first month
oftreatment, CK, AST,ALT and LDH levels decreased. The
steroiddosewasgraduallydecreasedandstopped.
Cyclophos-phamidetreatmentcontinuedforoneyearandattheendof
oneyear,thepatientwasstartedtobefollowedupwithonly
NSAIDs.
Case
2
A20-year-oldfemalepatienthadbeenfollowed-upwiththe
diagnosisofRAfortwoyears.Adalimumabhadbeenstarted
to the patient who had methotrexate resistance.
Follow-ingadalimumabtreatment,thecomplaintsrelatedtojoints
completely hadregressed andin thesixth monthof
treat-ment,thepatienthadthecomplaintsofweakness,fatigue,
paininthearmsandlegs,anddifficultyclimbingthestairs,
which had gradually increasedwithin the last two weeks.
Uponphysicalexamination,therewasweaknessinthe
upper-lowerextremities.Therewasnodermatologicalinvolvement
inthepatient.AST,ALT,CK,andLDHwere1024U/L,307U/L,
4772U/L,and1701U/L,respectively.TSHandother
biochem-icaltests were normal.ANA(titer1/320) andanti Jo-1 was
positive.Anti-SSA,anti-RNP,c-ANCA,andp-ANCAwere
nega-tive.EMGfindingsrevealedmyopathyintheproximalmuscles.
Thedeltoidmusclebiopsywasconsistentwithmyositis.
Adal-imumab treatment stopped. Three days pulse steroid (1g)
treatmentwasadministeredwiththediagnosisofPM.
Adali-mumabwasswitchedtorituximab.Followingthetreatment,
CKlevelsrapidlydecreased.Inthe secondmonthfollowing
thetreatment,thesteroiddosewasdecreasedupto5mg/day.
Onthecontrolinthe16thmonth,therewerenocomplaints
andthepatientiscurrentlybeingfollowed-upwithrituximab
andmethotrexate.
Case
3
A 44-year-old female had been followed-up withthe
diag-nosisofRAforapproximatelysevenyears.Thepatienthad
beenusingadalimumab40mg/2weeksforthreeyears.
Fol-lowingadalimumabtreatment,allcomplaintsrelatedtothe
jointshaddecreased.However,thepatienthadthecomplaints
oferuptioninthearms,forehead,andaroundthenose,on
themetacarpophlangealjointsofhand,fatigue,difficultyin
climbingthestairsanddyspnea,whichincreasedwitheffort
withinlastfourweeks.Uponherphysicalexamination,there
wasweaknessinproximalmusclesofallextremitiesand
erup-tions consistentwitherythemaonthearms. Therewasno
arthritis or jointdeformity. Clinical evaluation showed
dif-fuse pulmonarycrackles. Sedimentationrate was40mm/h
(5–20),andC-reactiveprotein(CRP)was45mg/L(0–5).ASTwas
169U/L,CKwas1563U/L.ANAwasin1/320homogenous
pat-ternandanti-Jo-1waspositive.Anti-SSA,anti-RNP,c-ANCA,
and anti-dsDNAwere negative.There wasbilateral
infiltra-tioninchestradiography.ThoraxHRCTwasconsistentwith
interstitiallungdisease.EMGtestingconfirmedthepresence
of proximal myopathy. Muscle biopsy was consistent with
myositis.AllthesefindingssuggestedTNF-induced
dermato-myositisandinterstitiallunginvolvement.Three-daypulse
steroid(1g)treatmentinitiallystartedfollowed1g
cyclophos-phamideandrituximabtreatments.Followingthetreatment,
serumCKlevelsrapidlydecreased.Inthefirstmonth
follow-ingthetreatmentbiochemicaltestsdecreased.However,there
waspartialimprovementindyspnea.Thepatientisinthe8th
monthafterthetreatment,thepatient’ssymptomsrelatedto
interstitiallungdiseasecontinue.
Methods
Pubmed was searchedfrom 2003present using the terms:
“TNF-␣, anti-TNF-␣”, “dermatomyositis”, “polymyositis”,
“inflammatorymyopathy”,“etanercept”,“lenercept”,
592
rev bras reumatol.2017;57(6):590–595text articles in the English language were selected. Then
thefollowingco-indexingtermswere used:“pathogenesis”,
“pathophysiology”,“treatment”or“therapy”.Wedidn’t
con-sidercongressabstractsorunpublishedresults.Weincluded
allcaseswhereaclearbaselinediagnosiswasmadeandthe
onset of DM/PMwas recorded after the use of anti-TNF-␣
agents.
Discussion
WepresentedtwocasesofRAandacaseofASwhich
devel-opedPMandDMfollowinganti-TNFuse.Therewasprominent
clinical improvementin the two patients; however, in one
patientwhodevelopedDM,althoughtheclinicalfindingsof
myositisregressed, therewas partialimprovement in
pul-monaryfindings.
Total21patientshavebeenreportedwhomyositis
devel-oped associated with anti-TNF in previous studies in the
literature (Table 1).4–17 With the addition of our cases, at
thetotal24patients,5maleand14werefemale.5patients
were not identifiedgender. Themean age of patientswas
4383±1119.Therewere19patientswithRA,2patientswith
AS,1patientwithseronegativearthritis,1patientwithCrohn’s
diseaseand1patientwithjuvenileidiopathicarthritis.The
duration oftheprimary disease inmostpatientswas
sub-stantiallylonger.12 ofthepatients developedpolymyositis
andother12withdermatomyositis.4patientsdidnotreceive
DMARDs(disease-modifyinganti-rheumaticdrugs).Mostof
the patients were receiving methotrexate as DMARD (11
patients). 10 patients etanercept, 6 patients infiliximab, 5
patients adalimumab and 2patients were using lenarcept.
10patientshadpulmonaryinvolvement.ANAin18patients,
anti-jo1in7patients,anti-PM-Sclin1patient,anti-dsDNAin1
patient,anti-PL-7in1patient,anti-PL-12in1patient,anti-U1
RNPin1patientwerefoundpositive.
Corticosteroidtreatmentwasgiventoallpatients.Pulse
steroidto6patients,highdosesofsteroidsto5patientswere
given.Themajorityofpatientshadaresponsetotreatment.
Only2patientshadapartialresponsetotreatment.
There-fore, steroidtherapy seems successfulin myositisinduced
withTNFtherapy.AfterTNFblockade,durationofmyositis
developmentrangesfrom2weeksto2yearsinallpatients.
ThemostcommonautoantibodiesinpatientswereANAand
anti-jo-1antibody.
AntiJo-1(histidyl-tRNAsynthetase)isamyositisspecific
auto-antibodythat ismostfrequentlypositiveinidiopathic
inflammatorymyopathies(PMandDM).Althoughitis
posi-tiveatarateof20–30%inPM,itbecomespositiveatarateof
60–70%inpatientswithPMdevelopinginterstitialpulmonary
fibrosis.18Inpolymyositis,MHCIexpressionincreasesin
mus-clethat injured as aresult ofanunknown cause,such as
viralinfection,mechanicaltrauma,orischemicinjury.Finally,
solubleJo-1emerges.ByCD4+andCD8+cellactivationwith
solubleJo-1,bothhumoralandcellularimmuneresponseare
activatedandthiscouldcausemuscledamage.19
Thecurrenttreatmentstrategyforpatientswith
immune-mediatedinflammatorymyopathiesinvolvesfirst-line
treat-ment with corticosteroids, alone or in combination with
an immunosupressant such as methotrexate, azothioprine
ormycophenolate, andinmoreresistantcasesintravenous
immunoglobulin or biological therapy.20 Anecdotal reports
havesuggestedthatanti-TNF-␣agents(i.e.:infliximab,
etan-ercept,adalimumab)maybehelpfulinthetherapyofpatients
with activerefractory PM/DM.21 All the clinical trials done
to evaluateTNF-␣ antagonists used an uncontrolled
open-label design. Conflicting results were obtained with both
the monoclonalantibodyinfliximaband the soluble
recep-tor etanercept.22 Although, more recent open-label studies
demonstratethatanti-TNF-␣agentsclearlyshownobenefit
inPM/DM.21
Differentsideeffectscoulddevelopdependingontheuse
ofanti-TNFdrugs.Autoimmunediseasesassociatedwith
anti-TNFuseisoneofthepossiblesideeffects.Themostcommonly
observed autoimmune diseases are vasculitic syndromes,
lupus-likesyndrome,psoriaticskinlesions,interstitiallung
diseases, sarcoidosis, autoimmune hepatitis, uveitis, and
antiphospholipidsyndrome.4,7,8,10,11,15,17,18,23Ofthese,lupus
and vasculitis are the most common,together comprising
60%ofdocumentedcasesofanti-TNFinducedautoimmune
disease.11 Anti-TNF induced dermatomyositis, however, is
rare,constitutinglessthanonepercentofreportedcasesof
anti-TNFinducedautoimmunity.Inthepreviousstudiesand
caseseries,anti-TNFtreatmenthasbeenshowntoincrease
muscleweaknessandexacerbatethedisease.24Moreover,the
incidenceofANA-positivityincreasesthreefoldwithanti-TNF
therapy,evenintheabsenceofalupus-likesyndrome.Oneof
theauto-immuneclinicalconditionsdevelopingsecondaryto
anti-TNFuseistheautoantibodypositivity.Themostcommon
autoimmune antibodypositivity are ANA and anti-dsDNA.
Althoughautoantibodydevelopmentisobservedwithall
anti-TNFagents,itisreportedtobemorefrequentwithinfliximab
use.25ANApositivityandJo-1antibodypositivitybefore
anti-TNFuseinthetwopatientswithRApresentedinthecurrent
casereportwerepreviouslyknown.Thus,ANApositivityand
Jo-1antibodypositivitywerenotduetoanti-TNFuse.However,
autoantibodiesinthepatientwithAShadnotbeenevaluated
beforeanti-TNFuse.Weretrievedallpublicationsandaddour
3casesdescribingthenewonsetofDM/PMafteranti-TNF
ther-apy(24patientstotal);ANApositivitywas33%(8cases)and
Jo-1 positivitywas20.3% (5cases).Inouropinion ANAand
Jo-1positivityinitiallyisnotacontraindicationforanti-TNF
therapyalone.However,thesepatientsshouldbeevaluated
carefully initiallyfor myositisand shouldbe closely
moni-toredduetothepotentialfordevelopingmyositisintreatment
process.
Inourcaseseries;PMor DMdevelopedinpatients who
usedanti-TNFtherapy.Patientshavenotgotanyclinical
find-ings associatedwithmyositisbeforeanti-TNFtherapy. Two
patientshadinflammatoryarthritisforseveralyearsandwas
thoughttobeassociatedwithRA.Inflammatoryarthritismay
occuralsointhemyositis.Therefore,itisthedifficultto
deter-mine whether myositisisanearlysymptom ofarthritisor
duetoanotherdiseaseinourtwopatients.Ourpatientwith
AShaveaxialinvolvement,soitiseasytodistinguishfrom
myositis.Therefore,itiseasiertoassociatetheanti-TNF
treat-mentwithmyositisinthispatient.However,ifmyositishad
beenduetoarthritisfromthebeginning,itisexpectedthatthe
complaintsofpatientsshouldincreaserapidlyinpatientswith
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7(6)
:590–595
593
Primary diagnosis/duration
Dmards Anti-TNF/duration Clinic Pul.invol. Treatment Treatment
Outcome
Antibodies
Case1
30/m
AS 10y
No Etanercept
2.5m
PM (−) MPpulse(1.0g) Improvement ANA1:160
Jo-1AntiJo-1
Case2
20/f
RA 2y
Mtx Adalimumab
6m
PM (−) MPpulse(1.0g) Improvement ANA1:320
Jo-1AntiJo-1
Case3
44/f
RA 7y
Mtx Adalimumab
36m
DM (+) MPpulse(1.0g),
CY
Partialresponse ANA1:320
Jo-1AntiJo-1
Musial20034
52/f
RA 20y
Mtx Infliximab
30m
PM (+) MPpulse(1.0g) Improvement ANA1:320
AntidsDNA1:20 Jo-1AntiJo-1
Flendrie20035,a RAa a a PM a a a a
Flendrie20056 52/f
RAa a Lenercepta DM a a Improvement a
Urata20067 52/f
RA 33y
Mtx Infliximab
9m
PM (+) 30mgMP Improvement ANA1:640
Jo-1AntiJo-1 Hall20068
44/f
RA 1y
Mtx Hcq
Etanercept 6m
DM (+) HighdoseMP,
AZP,MTX
Improvement ANA1:640
Jo-1AntiJo-1
Liozon20079 42/f
RA 1.5y
Mtx Hcq
Etanercept 9m
PM (+) HighdoseMP,CY Improvement ANA1:2560
Anti-PM-Scl Kiltz200810
57/f
RA 26y
Mtx Hcq
Etanercept 30m
PM (+) HighdoseMP,CY Improvement ANA1:2560
Kiltz200810 46/m
AS 17y
a Infliximab
6m
PM (−) a Improvement No
Ramos-Casals 200811 4patients
RAa a Infliximab(2p)
Etanerceptlenercept
PM(2p) DM(2p)
a a a a
Brunasso201012 45/f
RA 13y
No Adalimumab
34m
DM (−) MP Improvement ANA1:320
Klein201013 33/f
RAa No Etanercept
5m
DM (+) MP Improvement No
Klein201013 40/f
RAa No Etanercept
2y
DM (−) MP Partialresponse ANA
Klein201013 29/f
SNAa Mtx Adalimumab
3m
DM (−) MP,Mtx,AZP,
quinacrine
Improvement ANA1:640
Ishiguro201014 52/m
RA 12y
Mtx, Buc,Tac
Etanercept 26m
DM (+) MPpulse(1.0g) Improvement Anti-PL-7
Ishikawa20103 58/f
RA 2y
Buc,Tac Etanercept
2m
PM (+) MPpulse(0.5g) Improvement ANA1:320
Jo-1AntiJo-1 Ishikawa201115
63/f
RA 6m
Buc,Tac Etanercept
2m
PM (+) PSL1mg/kg Improvement ANA1:160
594
rev bras reumatol.2017;57(6):590–595 T able 1 – ( Continued ) Primar y dia gnosis/dur ation Dmar ds Anti-TNF/dur ation Clinic Pul. in v ol. T reatment T reatment Outcome Antibodies Riolo , 2012 16 36/m Cr ohn 1y Mtx Adalim uma b 2w Inflixima b 1 m DM (− ) MP , Mtx Impr o v ement AN A 1:640 Anti-U1 RNP Liu 2013 17 46/m JIA 36y Mtx Etaner ce pt 10y Adalim uma b 2 w eeks DM (− ) MP , Mtx Impr o v ement No y, y ear; m, month; AS , ank ylosing spond ylitis; RA, rheumatoid arthritis; JIA, juv enile idiopathic arthritis; PM, pol ym y ositis; DM, dermatom y ositis; HCQ, h ydr o xyc hlor oquine; Mtx, methotr e xate; Buc, bucillamine; T ac, tacr olim us; AZP , azathioprine; MP , meth ylpr ednisolone; CY , cyclophosphamide; AN A, Antin uclear antibod y; Anti dsDN A, anti doub le str anded DN A; Pul.˙ Inv
ol, pulmonar y in v olv ement; m, male; f, female; SN A, ser one g ati v e arthritis; w, w eek; PSL, pr ednisolone; Dmar ds, disease-modifying antirheumatic drugs. a Not done or not described.
aftertheanti-TNFtherapy.Thepatternofarthritis,deformity
anderosionwillhelptothedifferentialdiagnosis.
Anotherpossibilityistheoverlapsyndrome.Inflammatory
myositiscouldbeobservedasapartofoverlapsyndromewith
otherrheumatologicdiseases.Myositismostfrequently
over-lapswithRA,systemiclupuserythematosusandscleroderma.
AranbiciaAguilaetal.26reviewed220caseswithinflammatory
myositisinterms ofoverlapsyndrome.Theyfoundoverlap
syndrome in31 patients (9 DM, 22PM); however, systemic
sclerosiswasdetectedin15patients,SLEwasdetectedinnine
patientsandRAwasdetectedinsevenpatients.Myositisrarely
overlapswithotherconnectivetissuediseasesbuttheexact
incidenceisnotknown.
TNF-␣ is a cytokine produced mainly by activated
macrophages and T-lymphocytes. It is an essential
pro-inflammatory mediator and is implicated in the
patho-genesis ofmultiple immune-mediated inflammatory
disor-ders,including inflammatorymyopathies. Thereisgrowing
evidence that excessive production of pro-inflammatory
cytokines, and inparticularTNF-␣, maybeinvolved inthe
pathogenesisofidiopathicinflammatorymyopathies.27
TNF-␣anditsreceptorsareincreasedinmyositis.Suggestingarole
inthisdiseaseandmaybeusedintherapybutonthe
con-trary,itwasobservedthattreatmentofanti-TNFmayrisethe
exacerbate.Thereasonforthisisnotfullyunderstood.Two
possiblecauseshavebeensuggested.Firstly,accordingtothe
cytokine-shifthypothesis; TNF-␣ inhibitionwillchange the
balanceincytokineproductionasThelper-1andThelper-2
andpromotesthetype1interferonproduction.Type-1
inter-feron hasbeenshowntobeincreasedandthe playrolein
thepathogenesisinpatientswithmyositis.Thesecond
pos-siblecauseisincreasetheproductionofautoantibodieswith
the TNFblockadeinterferetoapoptosis.For example,after
theTNFblockadeinpatientswithRA,ANAandanti-dsDNA
antibodiesincreasedthatisknown.13
TNFinhibitorsareimportantdrugsusedinthetreatmentof
autoinflammatorydiseases.Theycanrarelyinducethe
devel-opmentofmyositisbesidestheknowntheirsideeffectssuch
asinfections,congestiveheartfailure,demyelinatingdiseases
and autoimmune diseases.Whencomplaintsarise suchas
shortnessofbreath,muscleweaknessandskinrash,patients
whotakeTNFtreatmentshouldbeevaluatedformyositis.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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