Rev. Bras. Reumatol. vol.57 número2

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ww w . r e u m a t o l o g i a . c o m . b r

REVISTA

BRASILEIRA

DE

REUMATOLOGIA

Original

article

Has

the

median

nerve

involvement

in

rheumatoid

arthritis

been

overemphasized?

Rajalingham

Sakthiswary

a,∗

,

Rajesh

Singh

b

a_Universiti_Kebangsaan_Malaysia_Medical_Centre_(UKMMC),_Department_of_Medicine,_Cheras,_Malaysia

b_Monash_University_Malaysia,_Jeffrey_Cheah_School_of_Medicine_and_Health_Sciences,_Department_of_{Orthopaedics,}_Bandar_Sunway,

Malaysia

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Articlehistory:

Received18September2015 Accepted5July2016

Availableonline30September2016

Keywords:

Mediannerve Rheumatoidarthritis Carpaltunnelsyndrome

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b

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Rheumatoidarthritis(RA)isawellandwidelyrecognizedcauseofcarpaltunnelsyndrome (CTS).Intherheumatoidwrist,synovialexpansion,jointerosionsandligamentouslaxity resultincompressionofthemediannerveduetoincreasedintracarpalpressure.We evalu-atedthepublishedstudiestodeterminetheprevalenceofCTSandthecharacteristicsofthe mediannerveinRAanditsassociationwithclinicalparameterssuchasdiseaseactivity, dis-easedurationandseropositivity.Atotalof13studiesmettheeligibilitycriteria.Pooleddata from8studieswithrandomselectionofRApatientsrevealedthat86outof1561(5.5%) sub-jectshadCTS.SubclinicalCTS,ontheotherhand,hadapooledprevalenceof14.0%(30/215). ThecrosssectionalareaofthemediannerveoftheRApatientswithoutCTSweresimilarto thehealthycontrols.Thevastmajorityofthestudies(8/13)disclosednosignificant relation-shipbetweenthemediannervefindingsandtheclinicalorlaboratoryparametersinRA.The linkbetweenRAandthemediannerveabnormalitieshasbeenoveremphasizedthroughout theliterature.TheprevalenceofCTSinRAissimilartothegeneralpopulationwithoutany correlationbetweenthemediannervecharacteristicsandtheclinicalparametersofRA.

O

envolvimento

do

nervo

mediano

na

artrite

reumatoide

tem

sido

excessivamente

valorizado?

Palavras-chave:

Nervomediano Artritereumatoide Síndromedotúneldocarpo

r

e

s

u

m

o

Aartritereumatoide(AR)éumacausabemeamplamentereconhecidadesíndromedotúnel docarpo(STC).Nopunhoacometidopelaartritereumatoide,aexpansãosinovial,aserosões articulareseafrouxidãoligamentarresultamemcompressãodonervomedianodecorrente doaumentoda pressão intracarpal.Avaliaram-se os estudospublicados para determi-naraprevalênciadeSTCeascaracterísticasdonervomedianonaAResuaassociação comparâmetros clínicos, como a atividadee duração da doençae a soropositividade.

∗ _{Corresponding}_author_.

E-mail:sakthis5@hotmail.com(R.Sakthiswary). http://dx.doi.org/10.1016/j.rbre.2016.09.001

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Preencheramoscritériosdeelegibilidade13estudos.Osdadosagrupadosdosoitoestudos comseleçãoaleatóriadepacientescomARrevelaramque86de1.561(5,5%)indivíduos tin-hamSTC.Poroutrolado,aSTCsubclínicateveumaprevalênciacombinadade14%(30/215). AáreadeseçãotransversadonervomedianodospacientescomARsemSTCfoisemelhante àdecontrolessaudáveis.Agrandemaioriadosestudos(8/13)nãoapresentourelação signi-ficativaentreosachadosnonervomedianoeosparâmetrosclínicosoulaboratoriaisnaAR. AligaçãoentreaAReasanormalidadesdonervomedianofoiexcessivamentevalorizada emtodaaliteratura.AprevalênciadeSTCnaARésemelhanteàdapopulaçãoemgeral, semqualquercorrelaçãoentreascaracterísticasdonervomedianoeosparâmetrosclínicos daAR.

Introduction

Beyondthejoints,rheumatoidarthritis(RA)maypresentwith extra-articular manifestations such as pulmonary fibrosis,

subcutaneousnodules and peripheralneuropathy in up to

10–20%ofpatients.1_The_wrist_is_the_most_frequently_affected jointinRAwithcarpaltunnelsyndrome(CTS)asapotential sequelae.Intherheumatoidwrist,synovialexpansion,joint erosionsandligamentouslaxityresultinlossofcarpaltunnel heightandincreasedcarpaltunnelpressure.Thiscontributes

to impaired axonal transport, compression of the median

nerveandvesselsintheperineuriumcausingmediannerve ischemia.2,3_The_other_plausible_culprit_mechanisms_that_have beenimplicatedinrheumatoidneuropathyaredrugtoxicity, vasculitisandamyloidosis.4

Carpal tunnelsyndrome(CTS) isbyand large aclinical diagnosis,althoughelectrophysiologicaltests(nerve conduc-tionstudies[NCS],electromyography[EMG])andsonographic

assessment of the median nerve may be useful to

sup-portthediagnosis,detectsubclinicalCTSandruleoutother abnormalities.5_{Unfortunately,}_the_neuropathic_pain_in_RA_is oftenoverlookedandmistakenforarthriticpain.6

Hartetal.wasthefirst todescribeneuropathyinRAin year1957.7_Since_then,_several_{electrophysiological}_and sono-graphicstudieshaveexaminedthemediannerveinRAwith variable findings.Thepurposeofthis systematicreview, is therefore,tosummarize theresultsofthesestudiesand to determineinRAtheprevalenceofCTS,characteristicsofthe mediannerveanditsassociationwiththeclinicalparameters suchasdiseaseactivity,diseasedurationandseropositivity.

Methods

Searchstrategy

We searched the literature for clinical studies on median nerve inRA usingthe followingdatabases:Science Direct, Pubmed/Medline,Ovid,ISIWebofKnowledge,EBSCOand Sco-pus.These searchterms used were “rheumatoidarthritis”, “mediannerve,”“carpaltunnelsyndrome”and“neuropathy”. Toensurecompleteness,wewentthroughpapersnotonlyon CTSexplicitlybutalsoonlessspecificconditionsthatmight encompassthemediannerve/CTSlikeperipheralneuropathy.

267 articles identified

245 excluded

: 16 - Other languages

: 46 - Case reports

- Unrelated studies/did not meet inclusion criteria : 183

8 excluded

: 8 - Unrelated studies/did not meet inclusion criteria 22 articles for full text article retrieval

14 studies included

Fig.1–Thealgorithmforselectionofstudiesinthis systematicreview.

Theabstractsofthestudieswerescrutinizedfor appropriate-nessbeforeretrievingthefulltextofthearticles.Wesearched thebibliographiesofallrelevantpublishedarticlestoavoid missingother relevantstudies.Fig.1summarizesthe algo-rithmusedforselectionofthestudies.Ethicsapprovalwas notrequiredforthissystematicreviewastherewasno recruit-mentofsubjectsorresearchintervention.

Selectioncriteria

Inclusioncriteria

The search was further refined to achieve a high level of homogeneityacrosstheselectedstudies.Weappliedatime restrictiontostudiespublishedfromyear1980onwards.We includedstudiesaboutRAwhich:

1. examinedthemediannervecharacteristics(sonographic and/orelectrophysiological),

2. wereaboutCTS,

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Exclusioncriteria

We excluded case reports and review articles. Studies on peripheralneuropathywhichdidnotprovidespecificdataon themediannervewerenotconsideredeither.

Dataextraction

Thefollowingdatawereextractedfromallstudiesincludedin thissystematicreview:studydesign,studypopulation includ-ing the detailsofthe controlarm, samplesize, prevalence

of CTS in RA, median nerve characteristics in RA

(sono-graphicand electrophysiological), the relationship between themediannervecharacteristicsandtheclinicalparameters. Therelevantandespeciallysignificantstatisticalvalues(pand

rvalues)wererecorded.

Results

Atotalof13studies.6,8–19_met_the_eligibility_criteria._Majority ofthestudies(12/13)werecross-sectional,andtherewere5 case-controlstudies.9,10,12,13,18_The_controls_employed_by_the studieswereeitherhealthyindividuals9,10,13,18_or_RA_patients withoutsymptomsofCTS.9_Study_sample_sizes_varied_from 2314_to₁₀₇₀16_subjects._Two_of_the_studies11,14_dealt_with sub-clinicalCTSi.e.conductedamongsubjectswithoutsignsand symptomsofCTS.Tables1and2highlightthefindingsofthe selectedstudies.

PrevalenceofCTSinRA

Inmoststudies,thediagnosisofCTSwasbasedona combi-nationofsymptoms(paraesthesia,tinglingsensation,painat themediannerveinnervatedarea),signs(positiveTinel’sor Phalentest)andelectrophysiologicalfindings.Theexact diag-nosticcriteriaanddefinitionofCTSusedacrossthestudies werequitediverse.Hammeretal.12_defined_CTS_based_on_a palm-to-wristmediansensorynerveactionpotential(SNAP) onsetlatencyof>2.0msorabsenceofSNAPandmediandistal motorlatencyof>4.9mswhereasSimetal.18_defined_CTS_as apalmtowristmediannervelatencyoflessthan50%.The prevalenceofCTSinRArangedfrom3.5%16_to_22.8%.17_Pooled datafrom8studies6,8,9,13,15–17,19_with_random_selection_of_RA patientsrevealedthat86outof1561(5.5%)subjectshadCTS. SubclinicalCTS,ontheotherhand,hadapooledprevalence of14.0%(30/215)(Table2).

SonographicfindingsofthemediannerveinRA

Cross-sectionalarea (CSA) ofthe mediannerve was deter-mined using ultrasound scan in 3of the studies.11–13 _Two outof3ofthesestudies12,13_were_of_{case–control}_design_with healthyindividualsascontrols.Hammeretal.11_investigated RApatientswithoutsignsandsymptomsofCTS.TheCSAof thebilateral mediannerve oftheRApatients withoutCTS weresimilartothehealthycontrols.Themean(standard devi-ation)oftherightmediannerveinasymptomaticRApatients was8.3(1.5)mm2_whereas_for_the_left_median_nerve_was_8.3 (1.4)mm2_.11_The_CSA_of_the_median_nerve_in_CTS_patients_were significantlyhigherwithamedianof15.7mm2_{(11.1–21.8).}12

ElectrophysiologicalfindingsofthemediannerveinRA

Electrophysiologicalassessmentofthemediannervewas car-riedoutin10/136,8–10,12,14–16,18,19_of_the_studies._Details_of_the NCS intermsofthe mediannerve velocity,amplitude and latencywereprovidedonlyby2studiesi.e.Lanzilloetal.10 andCalderetal.15_The_former_study_reported_that_the_median nervesensoryconductionvelocitywasreducedby25.2%along thedistalnervesegmentin57.5% ofRApatientscompared

to the general population. The amplitude of the sensory

responseswassignificantlyreducedatthewristandelbow in 17.5% and 5%ofpatients, respectively. Distal latencyto the abductorpollicisbrevismusclewassignificantlyslower in10%ofthepatientswhereasthemaximumvelocityfrom

the elbowto the wrist was prolonged by 12% in almost a

quarterofthesubjects.Calderetal.,10_found_that_the_median nerveSNAPamplitudewassignificantlylowerintheRAand handosteoarthritisgroupscomparedtothehealthycontrols (p<0.05) but there were no appreciable differences in the mediannerveSNAPconductionvelocityandlatencybetween theRApatientsandthehealthycontrols.Itisnoteworthythat thisstudyhadanextremelysmallsamplesizewithonly8RA patients.

Correlationbetweenthemediannervecharacteristicsand theclinicalparameters

Across the studies, the most frequently assessed clinical parameter was disease duration (9/13 studies)6,8,11,13–18 _as comparedtodiseaseactivity(4/13studies).6,8,9,13_Apart_from

the above mentioned, the following clinical and

labora-tory parameters were commonly analyzed by the selected

studies; age, height, weight, medications, rheumatoid fac-tor(RF),erythrocytesedimentationrate(ESR)andC-reactive

protein (CRP). Approximately half of these studies were

designed to compare the patients’ characteristics between RApatientswithandwithoutCTS13,16 _or_with_and _without neuropathy.6,8,17,18_The_vast_majority_of_the_studies_(8/13) dis-closednosignificantrelationshipbetweenthemediannerve involvementandclinicalorlaboratoryparametersinRA. How-ever,Karadagetal.13_and_Biswas_et_al.6_revealed_a_significant associationbetweendiseasedurationandtheoccurrenceof CTS (p=0.036)andneuropathy(p=0.001),respectively. Like-wise,2studiesfoundthatagewassignificantlyhigheramong RApatientswithCTS13_and_peripheral_neuropathy.18

Discussion

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Table1–SummaryoftheselectedstudiesofCTSinRA.

Ref. Test(s) Studypopulation Prevalence

ofCTSinRA n(%)

Clinicaland laboratory parameters

Findings

Lanzilloetal., 1998

NCSofperipheral nerves

40RApatients 5(12.5%) Age,disease

duration,steroid therapy,functional stage

Theelectrophysiologic findingswereunrelatedto clinicalfeaturesofRA.

Sivrietal., 1999

NCSand somatosensorial evokedpotential studies

33RApatientsand 20healthycontrols

2(6%) Nocorrelationbetween

neuropathyandtheclinical variables.

Sakinietal., 2005

NCS,EMG 80RApatients 8(22.8%) Diseaseduration Therewasnoassociation

betweendiseaseduration andtheoccurrenceof neuropathy.

Hammer etal.,2006

USofthemedian nervesatthe entranceofthe carpaltunnel,NCS, Tinel’sandPhalen’s tests.

7RApatientswith CTSsymptoms 5patientswithother formsofarthritis withCTSsymptoms Controls:30RA patientswithout symptomsofCTS& 30healthycontrols

Height,weight CSAofthemediannerves weresignificantlyhigherin theCTSpatientscompared withtheRAcontrolsand healthypersons;median (range)areaswere 15.7mm2_{(11.1–21.8),} 8.5mm2_(5.8–11.0)_and 8.0mm2_{(4.9–12.0),} respectively(p<0.0001). Nosignificantcorrelation betweenCSAofmedian nerveandclinical parametersintheRA group.Healthycontrolshad significantcorrelation betweenCSAofmedian nerveandheight(r=0.6, p<0.001)andweight (r=0.43,p=0.001) Agarwal

etal.,2008

NCSofperipheral nerves

108RApatients 11(10.1%) Absenceofdeep tendonjerks, extra-articular manifestations (interstitiallung disease,vasculitis, subcutaneous nodules),disease duration,RF,joint erosions,joint deformities, DMARDsor glucocorticoid intake,anddisease activity,abdominal fatpadforamyloid

Absenceofdeeptendon jerks(p<0.005)and vasculitis(p<0.01)were conspicuousinthe neuropathicgroup.There wasnorelationship betweenneuropathyand otherparameters.

Aktekinetal., 2009

EMGandNCSofthe peripheralnerves

56RApatients 32healthycontrols

2(4%) Corticosteroid

therapy,Schirmer’s test,RF,disease activity

Therewasnocorrelation betweenelectrophysiologic findingsandtheother studyparameters. Biswasetal.,

2011

NCSofthe peripheralnerves

74RApatients 3(10.3) Age,disease

duration,disease activity,RF, interstitiallung disease, subcutaneous nodules,vasculitis, corticosteroids, DMARDsandjoint erosions

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Table1– (Continued₎

Ref. Test(s) Studypopulation Prevalence

ofCTSinRA n(%)

Findings

Calderetal., 2012

NCSofthe peripheralnerves, sensorymapping (SM),vibratoryand currentperception thresholds(VPTand CPT)ofthe2ndand 5thdigits

7womenwithRA 9healthywomen 11womenwith handOA

AllSNAPamplitudeswere significantlylowerforthe handOAandhandRA groupscomparedwiththe healthygroup(p<0.05).No groupdifferenceswere foundforSNAPconduction velocities,SM,VPT,and CPT.

Karadag etal.,2012

Katzhanddiagram, BostonCTS questionnaire, PhalenandTinel tests.

USofwristjoints andcarpaltunnel grayscaleandpower Doppler.

Patientswith mediannerveCSA between10.0and 13.0mm2_were evaluatedwith electromyography (EMG)

100RApatients 45healthycontrols

18(18%) Age,gender,body massindex,disease duration,goiter, diseaseactivity, HAQ-DI,ESR,CRP, CTSglobal assessment,CTS symptomduration, Bostonsymptom severityscore, Bostonfunctional status

InRAgroupwithCTS:age (57[36–73]vs.50[24–76], p=0.041),historyofDM (35.3%vs.6.0%,p<0.001), diseaseduration(108 [12–396]monthsvs.72 [6–360]months,p=0.036), HAQ-DIscore(1.93 [0.75–2.87]vs.1.13[0–2.75], p=0.013),CTSpatient globalscore(52[1–97]vs.25 [0–91],p=0.001),Boston symptomseverity(2.81 [1.18–4.17]vs.2.0[1.0–4.01], p=0.01)andfunctional statusscores(3.37[1.37–5.0] vs.2.25[1.0–5.0],p=0.008) wereelevatedcomparedto patientswithoutCTS. Simetal.,

2014

NCS,Neuropathic SymptomsScale (NSS)

30RApatientswith symptomsof peripheral neuropathy

7(23.3%) Age,anti-CCP,the typeofmedication, diseaseduration, functionalstatus, neuropathic symptoms,ESR,CRP

Themeanagesofthe patientswithandwithout peripheralneuropathywere 69.4and56.5years, respectively(p<0.05).

Leeetal., 2015

EMG,NCS,Phalen’s andTinel’stests

1070RApatients 37(3.5%) CRP,disease duration

Therewasnostatistically significantcorrelation betweenCTSoccurrence anddurationofRAandCRP levels.

EMG,electromyography;NCS,nerveconductionstudies;RF,rheumatoidfactor;ESR,erythrocytesedimentationrate;CRP,C-reactiveprotein; CTS,carpaltunnelsyndrome;RA,rheumatoidarthritis;HAQ-DI,HealthAssessmentQuestionnaire–disabilityindex;OA,osteoarthritis;DMARD, diseasemodifyingantirheumaticdrug.

14.0%waswithinthereportedrangeinthegeneralpopulation of7–16%.24

Inhealthyindividuals,themeanCSAofthemediannerve atthelevelofentranceintothecarpaltunnel,whichhasthe highestdiagnosticsensitivityandspecificityforCTS,hasbeen foundto bebetween 7.0±1.0mm2 _and _10.2_±_2.5_mm2_.25–27

ThemeanCSAofthemediannerveinRApatientswithout

signsandsymptomsofCTSweresimilartohealthycontrols. Thislendscredencetothenotionthatthechronic inflamma-toryprocessesinRAdonotaffectthesizeofthemediannerve despitethecloseproximitybetweenthemediannerveand thewristjoint.However,Yagcietal.28_had_{contradicting} find-ingsofRApatientshavinglargerCSAofthemediannerve despiteabsence ofclinicalandneurophysiological evidence ofCTS.

No firm conclusions can be made on the

electrophysi-ological changes of the median nerve in RA owing to the

paucityofstudiesinthisregardandtheconflictingfindings oftheexistingstudies.AlthoughLanzilloetal.15_revealed_that morethanhalfofRApatientswithoutsymptomsofCTShad reducedmediannervesensoryconductionvelocityalongthe distalnerve segment,this study failedtodemonstrate any correlationbetweentheclinicalparametersofRAandthe elec-trophysiologicalfindings.Ofnote,thisstudyhadthedrawback ofnothavingacontrolarmandtherefore,comparisonwas madewithdatafromotherpublishedstudies.

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Table2–SummaryoftheselectedstudiesofsubclinicalCTSinRA.

Reference Test(s) Studypopulation Prevalenceof

subclinical CTSinRA

n(%)

Findings

Langetal.,1981 NCSof6 sensory nerves

23RA patients

5(21.7%) Age,gender, diseaseduration, stageofdisease, RF,ESR.

Nosignificantcorrelationbetween neurophysiological/neurological findingsandotherstudy parameters.

Hammeretal.,2007 USofthe median nervesatthe entranceof thecarpal tunnel

154RA patients withoutsigns and symptomsof CTS

10% Height,weight,

age,gender, diseaseduration, useof

prednisolone.

TheCSAofthemediannerves rangedfrom5.0to12.8mm2_,_with the97.5centilebeing11.1mm2_. Themeancross-sectionalareasof themediannerveinpatientswith RAweresimilartothosereported inhealthycontrols.

Nosignificantassociationbetween CSAofmediannerveandall studiedparametersexceptfor gender;malesweresignificantly higher(8.8±1.3mm2_versus females:8.0±1.4mm2_[_p_,_0.001]

NCS,nerveconductionstudies;RF,rheumatoidfactor;ESR,erythrocytesedimentationrate;CTS,carpaltunnelsyndrome;RA,rheumatoid arthritis.

scores were higher among the RA patients with CTS, the

remaining studies were not in agreement with the above

findings.However,numerousstudieswhichinvestigatedthe extra-articular manifestations of RA, in general, identified thefollowing factorsas predictorsin thisregard:high dis-easeactivity,smoking,antinuclearantibodiesandrheumatoid nodules.29,30

Thestudies includedinthissystematicreviewwere not withouttheirindividuallimitations.Inparticular,manyhad a small sample size, hence limiting the statistical power. Many of the studies did not fully control for confounding

factors of CTS such as occupation, the presence of

dia-betesmellitusandhypothyroidism.DefinitionofCTSvaried substantiallyacrossthestudies.MisclassificationasCTS, par-ticularlyamongstudiesthatdiagnosedCTSsolelybasedon symptoms,wasanotherpotentialsourceoferror.

Inconclusion,thenexusbetweenRAandthemediannerve

abnormalitiesorCTShasbeenoveremphasized throughout

theliterature.Basedonthissystematicreview,asubstantial bodyofresearchsuggeststhattheprevalenceofCTSinRA issimilartothegeneralpopulationwithoutanycorrelation betweenthemediannervefindingsandtheclinical parame-tersofRA.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgements

Theauthorwould liketothankthelibrariansof“Universiti KebangsaanMalaysia”fortheirassistanceinretrievingthefull textofthearticles.

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