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www.elsevier .es / rcreuma

Artculo de revisin

Polimialgia reumtica

Ronald Leonel Garca Ariasa,, Juan Martn Gutirrezb, Mara Claudia Dazb

y Daniel G. Fernndez-vilab

a Unidad de Geriatra, Departamento de Medicina Interna, Hospital Universitario San Ignacio - Pontificia Universidad Javeriana,

Bogot, Colombiab Unidad de Reumatologa, Departamento de Medicina Interna, Hospital Universitario San Ignacio - Pontificia Universidad Javeriana,

Grupo Javeriano de Investigacin en Enfermedades Reumticas, Bogot, Colombia

informacin del artculo

Historia del artculo:

Recibido el 15 de abril de 2014

Aceptado el 16 de abril de 2015

On-line el3 de junio de2015

Palabras clave:

Polimialgia reumtica

Arteritis de clulas gigantes

CorticosteroidesDolor

Mialgia

r e s u m e n

La polimialgia reumtica es una enfermedad inflamatoria crnica comn en la poblacin

geritrica. Su cuadro clnico se caracteriza por dolor en la cintura escapular, regin cervical

y caderas, asociado frecuentemente a rigidez de estas reas articulares posterior a periodos

de reposo. El diagnstico de esta patologa es clnico y debe hacerse posterior a descartar

otras entidades como artritis reumatoide o espondiloartropata de aparicin tarda. Hasta

el momento,no hay criteriosde clasificacinestandarizados y aceptados, por lo querecien-

temente se desarrollaron unos criterios provisionales por parte del Colegio Americano de

Reumatologay de laLiga Europea Contrael Reumatismo.La polimialgia reumticase asocia

hasta en un 30% de los pacientes con arteritis de clulas gigantes. El principal tratamientoes con dosis bajas de glucocorticoides, con lo cual los pacientes presentan rpida mejora

sintomtica. 2014 Asociacin Colombiana de Reumatologa. Publicadopor Elsevier Espaa, S.L.U.

Todos los derechos reservados.

Polymyalgia rheumatica

Keywords:

Polymyalgia rheumatica

Giant cell arteritisGlucocorticoids

Pain

Myalgia

a b s t r a c t

Polymyalgia rheumatica is an inflammatory disease common in the geriatric population.

The clinical profile is characterized by pain, mainly in the shoulder girdle, hip and cervical

region.Thediagnosisofthisdisease isclinical,andshouldbemade torule outanotherdisea-ses suchas lateonsetrheumatoidarthritisandspondyloarthritis.Althoughno standardized

classificationcriteria havebeen accepted, although there aresome,yet to be evaluated, pro-

visional classification criteria that have recently been developed by the American College

ofRheumatology and European League Against Rheumatism. The polymyalgia rheumatica

Autor para correspondencia.Correo electrnico: [email protected] (R.L. Garca Arias).

http://dx.doi.org/10.1016/j.rcreu.2015.04.0020121-8123/ 2014 Asociacin Colombiana de Reumatologa. Publicado por Elsevier Espaa, S.L.U. Todos los derechos reservados.

en o escarga o e p: www.elsevier.es el . opia para uso personal, se pro e la ransmisi n e es e ocumen o por cualquier me io o orma o.
http://localhost/var/www/apps/conversion/tmp/scratch_3/dx.doi.org/10.1016/j.rcreu.2015.04.002http://localhost/var/www/apps/conversion/tmp/scratch_3/dx.doi.org/10.1016/j.rcreu.2015.04.002http://localhost/var/www/apps/conversion/tmp/scratch_3/dx.doi.org/10.1016/j.rcreu.2015.04.002http://localhost/var/www/apps/conversion/tmp/scratch_3/dx.doi.org/10.1016/j.rcreu.2015.04.002http://localhost/var/www/apps/conversion/tmp/scratch_3/dx.doi.org/10.1016/j.rcreu.2015.04.002http://www.elsevier.es/rcreumamailto:[email protected]://localhost/var/www/apps/conversion/tmp/scratch_3/dx.doi.org/10.1016/j.rcreu.2015.04.002http://localhost/var/www/apps/conversion/tmp/scratch_3/dx.doi.org/10.1016/j.rcreu.2015.04.002mailto:[email protected]://crossmark.crossref.org/dialog/?doi=10.1016/j.rcreu.2015.04.002&domain=pdfhttp://www.elsevier.es/rcreumahttp://localhost/var/www/apps/conversion/tmp/scratch_3/dx.doi.org/10.1016/j.rcreu.2015.04.002

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r ev co lomb r eumato l . 2015 ;22(2):104109 105

is associated with up to 30% of patients with giant cell arteritis. The main treatment is

low-dose glucocorticoids, with whichpatients have rapid symptomatic improvement.

2014 Asociacin Colombiana de Reumatologa. Published by Elsevier Espaa, S.L.U.

All rights reserved.

Materiales y mtodos

Se realiz una bsqueda de literatura en las siguien-tes bases de datos: Medline, colaboracin Cochrane yCRD Data base. La bsqueda se restringi a los idiomasingls y espanol, artculos tipo revisin de tema, revi-sin sistemtica y artculos originales que hubiesen sidopublicados hasta marzo de 2014. Los trminosmesh emplea-dos fueron los siguientes: polymyalgia rheumatica[Mesh],glucocorticoids[Mesh], Myalgia[Mesh]. Se utilizaron losoperadores booleanos AND/OR para cada uno de los trmi-nos. Seobtuvieron171artculos, de loscualesse escogieron53

por consenso del grupo de autores, considerndose que estosbrindaban informacin acerca de los tpicos necesarios pararealizar la presente revisin. Conbase en la informacin obte-nida se realiz una revisinnarrativa acerca del diagnstico ytratamiento de la polimialgia reumtica (PMR) (fig. 1).

Epidemiologa

La PMR es una enfermedad tpica de pacientes ancianos. Seproduce casi exclusivamente enmayoresde 50 anosy laedadpromediode inicio esde73anos1. Su prevalencia se estimaen700/100.000 habitantesmayoresde 50 anos2. Setecientas once

mil personas en Estados Unidospresentan la enfermedad y latasa de incidencia es de 58,7 personas por cada 100.000 per-sonas/ano3. Su incidencia se incrementa con la edad y vara

Bsqueda en medline, colaboracincochrane y CRD data base de acuerdo

con trminos mesh

Total: 171 artculos

Revisin de ttulo y resumen

Inclusin de artculos tipo revisin de tema,revisin sistemtica y originales publicados

hasta marzo de 2014, segn consenso de losautores

Artculos incluidos: 53

Figura 1 Flujograma de seleccin de artculos.

segn la regingeogrficaestudiada,encontrandomayor inci-dencia en pases escandinavos y en personas descendientesdel norte de Europa1,4. Durante el primer ano de diagnstico,los pacientes utilizan ms los servicios de salud y estn pro-pensosa infarto delmiocardio, enfermedad arterial perifricay eventos cerebrovasculares5.La PMR se asocia con arteritis de clulas gigantes en el

30% de los pacientes. Clnicamente, 40-60% de los pacientescon arteritis de clulas gigantes tienen sntomas de PMR enel momento del diagnstico6. La PMR y la arteritis de clulasgigantes tienenmuchas similitudes (edad de inicio, predomi-nio en mujeres, distribucin geogrfica similar y, en ambas,documentacin de un estado inflamatorio crnico), lo cualsugiere que las dos entidades podran representar diferentestipos de una misma enfermedad.

Etiopatogenia

La causa de la PMR es desconocida y se ignora la razn de sumayor frecuencia entre lapoblacingeritrica. En lapatogne-sis de la enfermedad los estudios sugieren una base genticaasociadaa factoresambientales7. Dentrode lospolimorfismosgenticos relacionados con la regulacin inmune y asocia-dos con riesgo y gravedad de la enfermedad, se encuentran:la molcula de adhesin intercelular 1, los antagonistas delreceptor de interleucina 1 y la interleucina 68,9. La asociacinconalgunosantgenos,comoelHLADR4yHLADRB1,ascomocon agentes infecciosos, tales como Mycoplasma pneumoniae,parvovirusB19y Chlamydiapneumoniae, tienenresultadoscon-troversiales en los estudios y no pueden ser justificados aundentro de la patognesis de la enfermedad10.Se ha documentado como un importante mecanismo en

la fisiopatologa de la PMR, el aumento en la produccin localde citocinas proinflamatorias detectadas en el intersticio delos msculos y en sangre de pacientes con la enfermedad,principalmente interleucina 6 y cuyos valores disminuyende forma significativa con la remisin de los sntomas, pos-terior al tratamiento con corticosteriodes11. As mismo, elproceso de endocrino-senescencia que produce disminucinen losnivelesde dehidroepiandrosterona o androstenodionaylas alteraciones en el eje hipotalmico-pituitario-gonadal coninsuficiencia adrenal y disminucin de la secrecin de corti-solen respuestaal estadoinflamatorio, sehanpostuladocomomecanismos etiopatognicos de importancia12.

Manifestaciones clnicas

La PMR se caracteriza por dolor y rigidez de la cintura esca-pular, plvica y regin cervical. El cuadroclnico caractersticoes, por lo general, de duracin mayor a un mes, consistente


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Tabla 1 Diagnstico diferencial de la polimialgiareumtica

Enfermedades reumticas

Artritis reumatoideEspondiloartropatasArtritis por cristalesLupus eritematoso sistmico

VasculitisMiopatas inflamatorias

Enfermedades musculoesquelticas no inflamatorias

FibromialgiaCapsulitis adhesivaEnfermedad articular degenerativaEnfermedad delmanguito rotador

Endocrinopatas

Enfermedades tiroideasAlteraciones de la glndula paratiroidea

Infecciones

ViralesBacterias

MicobacteriasEnfermedades malignas

Slidas, hematolgicas

Miscelneos

ParkinsonismoDepresinHipovitaminosis DDrogas inductoras de miopata. Ej. estatinas

en dolor en la cintura escapular, bilateral, de predominio noc-turno, que aumenta con el reposo, asociado a rigidezmatinalque dificulta la realizacin de las actividades de la vida diaria,acompanndose de sntomas constitucionales como fatiga,

malestar general, anorexia, prdida de peso y fiebre que pue-den ocurrir en el 40-50% de los pacientes13.Dada la asociacin entre la PMR y la arteritis de clu-

las gigantes, es obligado identificar sntomas tales comocefalea, claudicacinmandibular, sensibilidaddel cuero cabe-lludo, carotidinia, alteraciones visuales y claudicacin deextremidades14.En el examen fsico se puede encontrar rigidez y dolor en

cintura escapular con incapacidad del individuo para la ele-vacinactiva de las extremidades superiores,mientras que lamovilizacin pasiva es normal. Adicionalmente, puede apa-recer dolor en la palpacin de los msculos sin tumefaccinarticular y la sinovitis articular puede verse en el 25% delos pacientes, la cual es transitoria, oligoarticular, de articu-laciones perifricas, principalmente compromiso de rodillas,carpos y metacarpofalngicas, de intensidad leve amoderaday sin produccin de erosiones ni destruccin articular15.

Diagnstico

EldiagnsticodelaPMR es fundamentalmenteclnico.Se deberealizar una exhaustiva historia clnica y un cuidadoso exa-men fsico para distinguirla de otras entidades (tabla 1).En la literatura se mencionan varios criterios de cla-

sificacin de PMR (Bird, Jones y Hazleman, Chuang y

Healey) ninguno de los cuales ha logrado estandarizacin

Tabla 2 Criterios provisionales de clasificacinde polimialgia reumtica

Criterios clnicos

Rigidez matinal >45minutos 2Dolor o limitacin en cadera 1FR o anti CCP negativo 2Ausencia de otra afeccin articular 1

Criterios ultrasonogrficos

Almenosun hombro conbursitis subdeltoidea o tenosinovitisbicipital o sinovitis 1 glenohumeral y al menosuna caderacon sinovitis o bursitis trocantricaAmbos hombros con bursitis subdeltoidea, tenosinovitisbicipital o sinovitis glenohumeral 1

Criterios requeridos: edad50 a nos, dolor de hombros bilateral,

aumento de VSG o PCR

Con solo criterios clnicos una puntuacin 4 tiene una sensibilidad

de 68% y una especificidad de 78% para diferenciar PMR de otros

trastornos

Con la combinacin de criterios clnicos y ecogrficos una puntuacin 5

tiene una sensibilidad de 66%y especificidad de 81% para diferenciar

PMRde otros trastornos

y aceptacin13,16,17 . Con el objetivo de lograr unos mejorescriterios clasificatorios de PMR, se desarroll una iniciativainternacional a cargode laLiga Europea Contra elReumatismoy del Colegio Americano de Reumatologa, entidades quedesarrollaronunoscriteriosde clasificacinprovisionalque sepublicaron en abril de 201218 (tabla 2). Estos criterios no hansido validados como criterios diagnsticos pues se trata decriterios de clasificacin, tiles para distinguir la polimialgiade otros trastornos y su aplicabilidad est orientada, funda-mentalmente, al campo de la investigacin. Se reporta unasensibilidad de 66% y especificidad de 81% para discrimi-

nar pacientes con la enfermedad, comparados con sujetoscontrol19.Los hallazgos de laboratorio son inespecficos y similares

a los de un proceso de inflamacin sistmica. Lo ms carac-terstico es la elevacin de la velocidad de sedimentacinglobular por encima de 40mm/h, sin embargo, valores bajos(30mm/h) o normales han sido reportados en 6-20% de lospacientes con la enfermedad20,21. La protenaC reactiva es unmarcador ms sensible de inflamacin en esta patologa22,23.El factor reumatoide, los anticuerpos antinucleares y los anti-cuerpos contra el pptido cclico citrulinado son negativos ysu positividad debe hacer reconsiderar el diagnstico24.En cuanto a las imgenes diagnsticas, la radiologa con-

vencional de las articulaciones afectadas suele ser normal, locual tambin sucede con los estudios electromiogrficos. Laultrasonografa frecuentemente detecta anormalidades de lasestructuras periarticulares y, de acuerdo con los nuevos crite-riosclasificatorios,mejora la especificidad parala clasificacinde PMR (tabla 2), siendo de utilidad en casos de pacientes conpolimialgia y marcadores inflamatorios normales25.La resonancia nuclear magntica muestra anormalidades

de estructuras periarticulares tales como bursitis subdeltoi-dea, subacromial y trocantrica, as como sinovitis26.El Pet Scan es un estudio costoso y no se usa de rutina en

pacientes con PMR. Se puede usar en la valoracin en pacien-tes con sntomas inexplicados o refractarios y sospecha de

neoplasia oculta o vasculitis27.


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Edad > 50 aos

Dolor bilateral en hombros

Dolor bilateral en caderas

Rigidez matutina > 45 minutos

Duracin > 1 mes

Elevacin de VSG - PCR

Sospecha clnica

Diagnstico diferencial

Infeccin

Fibromialgia

Cncer activo

Espondiloartritis

Artritis reumatoide

Miopata inflamatoria

Lupus eritematoso sistmico

Condiciones locales en caderas

Condiciones locales en hombros

Tratamiento

Seguimiento

Disminucin de dolor y rigidez > 70%

Disminucin en reactantes de fase aguda

No hay diagnstico alternativo diferente a PMR

Cuidados de efectos secundarios del corticosteroide

Suplencia de calcio ms vitamina D

Seguimiento metablico (glicemia, lpidos)

Disminucin progresiva en dosis de corticosteroide

Respuesta clnica rpida

Prednisolona 15 a 20 mg/da

Figura 2 Algoritmo diagnstico y teraputico en PMR.

La biopsia sinovial demuestra sinovitis, en menor gradoque en la artritis reumatoide. La biopsia de arteria temporalno est indicada de rutina y debe realizarse solamente antesospecha de arteritis de clulas gigantes6.

Tratamiento

El tratamientode eleccin en PMR son los glucocorticoides endosis bajas, con los que se logra una rpida resolucin de lossntomas, por lo general entre 24 a 72 horas, siendo consi-derados, incluso, como una prueba teraputica para ayudara confirmar el diagnstico, dada la excelente y rpida res-

puesta que usualmente tienen los pacientes con este tipo detratamiento.Ladosisrecomendadaesde15a20mgde prednisolona/da.

Dosis altas rara vez son necesarias a menos que exista sos-pecha de arteritis de clulas gigantes28. La dosis inicial deglucocorticoides debe mantenerse durante 2 a 4 semanas,para reducirla lentamente a razn de 2,5mgcada 2 a 4 sema-nas hasta una dosis de 10mg/da; esta dosis se utiliza comomantenimiento durante unmes, con posteriores reduccionesprogresivas en la dosis hasta suspenderla28,29.Lamayorade los pacientesrequierentratamiento durante

12 a 24meses. En ocasiones, tras la reduccin de la dosis, rea-parecen los sntomas, requiriendo aumentar nuevamente la

dosis hasta llegar a la que elimine los sntomas y, en algunos

casos,dosisbajasde glucocorticoides a largoplazopodran sernecesarias para prevenir estas recadas. En los casos leves oen pacientes con varias comorbilidades, la metilprednisolonaintramuscular a dosis inicial de 120mgcada 3 a 4 semanas,durante 3 meses, seguida de una reduccin de 20mgcada 2a 3 meses puede ser considerada30,31. Junto con la respuestaclnica, losmarcadores de inflamacin tambin se deben nor-malizar en pocas semanas de iniciado el tratamiento, si estono sucede deben considerarse otros diagnsticos.El uso crnico de glucocorticoides aumenta el riesgo de

osteoporosis32,33, por lo que en los pacientes ancianos estindicado administrar tratamiento profilctico paraprdida demasa sea con calcio y vitamina D, as como terapia con bis-

fosfonatos en pacientes de alto riesgo34,35.En cuantoal usode inmunomoduladores en pacientes con

PMR y alto riesgo de desarrollar efectos adversos relaciona-dos con el uso crnico de glucocorticoides o en pacientes conenfermedad recurrente, podra considerarse su uso36,37.El ms estudiado de los antirreumticos en PMR es el

metotrexate, sin embargo, debe tenerse en cuenta que estemedicamento ha sido probado en 3 ensayos clnicos aleato-rizados, encontrndose resultados diferentes; en 2 estudiosse demostr eficacia38,39 y en el tercero no se logr probarun efecto ahorradorde corticosteroides40. En cuanto a azatio-prina solo sedispone deunestudio, el cual se realiz enformaaleatorizada, doble ciego y controlado con placebo, demos-

trndose una disminucin en la dosis de prednisolona a la


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semana52, pero conun incremento en lafrecuencia deefectosadversos relacionados con la azatioprina, pero debe tenerseen cuenta que se trat de un estudio pequeno (31 pacientes)y solo el 65% de los sujetos en estudio completaron el tiempode seguimiento41.Por otra parte, hasta el momento no existe evidencia que

recomiende el uso de terapia biolgica, pero se investiga su

uso en pacientes con recadas, como es el caso de infliximab,el cual se prob en un ensayo clnico, multicntrico, aleato-rizado, comparado con placebo en 40 pacientes con PMR, aquienes se les administr infliximab y prednisolona vs. pla-cebo y prednisolona, documentndose igual tasa de recadasen ambos grupos42. Otros blancos teraputicos para terapiasbiolgicas estn siendo actualmente investigados, como es elcaso de terapias contra la IL-1, IL-6 e IL-17.

Pronstico

La calidad de vida de los pacientes con PMR usualmente seve comprometida desde el comienzo de la enfermedad, peromejora sustancialmente con el inicio del tratamiento43,44. Larespuesta al tratamientosevalora teniendoencuentalamejo-ra sintomtica y de los marcadores de inflamacin. Se debetener en cuenta que el 50% de los pacientes puede presentarrecadas45,46. El tratamiento inicial con dosis altas de esteroi-des o su rpido retiro, el sexo femenino y los niveles elevadosde PCR e IL 6 se asocian con riesgo de recadas47,48. Por otraparte, el aumento en el riesgode enfermedad vascular perif-rica genera la posibilidad de complicaciones vasculares49, sinembargo, la supervivencia de lospacientesconPMRes similara la de la poblacin general50,51.

Conclusin

La PMR es una enfermedad inflamatoria de causa descono-cida, muy rara enpersonasmenores de 50 a nos. La incidenciaaumenta con la edad con un pico en personas entre 70 y80anos, porlo cual debe sospecharseentodopacienteancianocondolor osteomuscular en la cintura escapular o plvica. Nohay exmenes especficos de la enfermedad y el diagnsticose fundamenta en la presentacin clnica y la usual eleva-cin de los reactantes de fase aguda (fig. 1). Se debe tener encuenta su asociacin frecuente con arteritis de clulas gigan-tes. Finalmente, cabe recordarqueel diagnsticode PMResdeexclusin, es decir, primero deben considerarse y descartarseotras enfermedades que pueden presentar sintomatologasimilar tales como artritis reumatoide y espondiloartropatasde aparicin tarda, enfermedades malignas, enfermedadesmetablicas e infecciosas. El tratamiento se basa en el usode corticoides, a dosis bajas, con los cuales la mejora clnicasuele ser rpida y marcada (fig. 2).

Conflicto de intereses

Los autores declaran no tener ningn conflicto de intereses.

b i b l i ogra f a

1. Doran MF, CrowsonCS, OFallonWM,Hunder GG,Gabriel SE.Trends in the incidence of polymyalgia rheumatica over a 30year period in Olmsted County, Minnesota, USA. J Rheumatol.2002;29:16947.

2. Lawrence RC, Helmick CG, Arnett FC. Estimates of theprevalence of arthritis and selectedmusculoskeletal disordersin the United States. Arthritis Rheum. 1998;41:77899.

3. CrowsonCS,Matteson EL,Myasoedova E. The lifetime riskofadult-onset rheumatoid arthritis and other inflammatoryautoimmune rheumatic diseases. Arthritis Rheum.2011;63:6339.

4. Gonzlez-Gay MA, Vzquez-Rodrguez TR, Lpez-DazMJ.Epidemiology of giant cell arteritis and polymyalgiarheumatic. Arthritis Rheum. 2009;61:145461.

5. Kremers HM, Reinalda MS, Crowson CS, Zinsmeister AR,Hunder GG, Gabriel SE. Directmedical costs of polymyalgiarheumatica. Arthritis Rheum. 2005;53:57884.

6. Salvarani C, Cantini F, Hunder GG. Polymyalgia rheumaticaand giant-cell arteritis. Lancet. 2008;372:23445.

7. Liozon E, Ouattara B, RhaiemK. Familial aggregation in giantcell arteritis and polymyalgia rheumatica: a comprehensiveliterature review including 4 new families. Clin ExpRheumatol. 2009;27:S8994.

8. Gonzlez-Gay MA, Amoli MM, Garca-Porrua C, OllierWE.Genetic markers of disease susceptibility andseverity in giantcell arteritis and polymyalgia rheumatica. Semin ArthritisRheum. 2003;33:3848.

9. lvarez-Rodrguez L, Carrasco-Marn E, Lpez-Hoyos M.Interleukin-1RN gene polymorphisms in elderly patients withrheumatic inflammatory chronic conditions: Association ofIL-1RN*2/2 genotype with polymyalgia rheumatica. HumImmunol. 2009;70:4954.

10. Elling P, Olsson AT, Elling H. Synchronous variations of theincidence of temporal arteritis and polymyalgia rheumatica

in different regions of Denmark; association with epidemicsofMycoplasmapneumoniae infection. J Rheumatol.1996;23:1129.

11. Kreiner F, Langberg H, Galbo H. Increasedmuscle interstitiallevels of inflammatory cytokines in polymyalgia rheumatica.Arthritis Rheum. 2010;62:376875.

12. StraubRH, CutoloM. Further evidence for insufficienthypothalamic-pituitary-glandular axes in polymyalgiarheumatica. J Rheumatol. 2006;33:121923.

13. Chuang TY, Hunder GG, Ilstrup DM, Kurland LT. Polymyalgiarheumatica: a 10-year epidemiologic and clinical study. AnnIntern Med. 1982;97:67280.

14. Salvarani C, Cantini F, Olivieri I, Hunder GS. Polymyalgiarheumatica: a disorder of extraarticular synovial structures.J Rheumatol. 1999;26:51721.

15. Salvarani C, Cantini F, Macchioni P. Distalmusculoskeletalmanifestations in polymyalgia rheumatica: a prospectivefollow up study. Arthritis Rheum. 1998;41:12216.

16. Bird HA, Esselinckx W, Dixon AS, Mowat AG, Wood PH. Anevaluation of criteria for polymyalgia rheumatica. AnnRheumDis. 1979;38:4349.

17. Healey LA. Long-term follow-up of polymyalgia rheumatica:evidence for synovitis. Semin Arthritis Rheum. 1984;13:3228.

18. Dasgupta B, Cimmino MA, Kremers HM. 2012 Provisionalclassification criteria for polymyalgia rheumatica: a EuropeanLeague against Rheumatism/American College ofRheumatology collaborative initiative. Arthritis Rheum.2012;64:94354.

19. Dasgupta B, Cimmino MA,Maradit-Kremers H. 2012provisional classification criteria for polymyalgia rheumatica:

a European League against Rheumatism/American College

http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0005http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0005http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0005http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0005http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0005http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0005http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0010http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0010http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0010http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0010http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0010http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0015http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0015http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0015http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0015http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0015http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0015http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0020http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0020http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0020http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0020http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0025http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0025http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0025http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0025http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0030http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0030http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0030http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0030http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0035http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0035http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0035http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0035http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0035http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0035http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0040http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0040http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0040http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0040http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0040http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0045http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0045http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0045http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0045http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0045http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0045http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0050http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0050http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0050http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0050http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0050http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0050http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0050http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0050http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0055http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0055http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0055http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0055http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0060http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0060http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0060http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0060http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0065http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0065http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0065http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0065http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0070http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0070http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0070http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0070http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0070http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0075http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0075http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0075http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0075http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0080http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0080http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0080http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0080http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0080http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0085http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0085http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0085http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0090http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0090http://refhub.elsevier.com/S0121-8123(15)00030-4/sbref0090http://refhu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of Rheumatology collaborative initiative. Ann RheumDis.2012;71:48492.

20. Ellis ME, Ralston S. The ESR in the diagnosis andmanagement of the polymyalgia rheumatica/giant cellarteritis syndrome. Ann RheumDis. 1983;42:16870.

21. Cantini F, Salvarani C, Olivieri I. Erythrocyte sedimentationrate and C-reactive protein in the evaluation of diseaseactivity and severity in polymyalgia rheumatica: a prospective

follow-up study. Semin Arthritis Rheum. 2000;30:1724.22. Kyle V, Cawston TE, Hazleman BL. Erythrocyte sedimentation

rate and C reactive protein in the assessment of polymyalgiarheumatica/giant cell arteritis on presentation and duringfollow up. Ann RheumDis. 1989;48:66771.

23. Kyle V, Wraight EP, Hazleman BL. Liver scan abnormalities inpolymyalgia rheumatica/giant cell arteritis. Clin Rheumatol.1991;10:2947.

24. Dasgupta B, HutchingsA, Hollywood J, Nutter L.Autoantibodies to cyclic citrullinated peptide in a PMRinception cohort from The PMROutcomes Study. Ann RheumDis. 2008;67:9034.

25. Cantini F, Salvarani C, Olivieri I. Inflamed shoulder structuresin polymyalgia rheumaticawith normal erythrocytesedimentation rate. Arthritis Rheum. 2001;44:11559.

26. McGonagleD, Pease C, Marzo-OrtegaH, OConnor P, GibbonW, Emery P. Comparison of extracapsular changes bymagnetic resonance imaging in patients with rheumatoidarthritis and polymyalgia rheumatica. J Rheumatol. 2001;28:183741.

27. Blockmans D, Bley T, Schmidt W. Imaging for large-vesselvasculitis. Curr Opin Rheumatol. 2009;21:1928.

28. Dasgupta B, Borg FA, Hassan N. BSR and BHPR guidelines forthe management of polymyalgia rheumatica. Rheumatology(Oxford). 2010;49:18690.

29. Hernndez-Rodrguez J, Cid MC, Lpez-SotoA, Espigol-FrigoleG, Bosch X. Treatment of polymyalgia rheumatica: asystematic review. Arch InternMed. 2009;169:183950.

30. Meskimen S, Cook TD, Blake RL. Management of giant cellarteritis andpolymyalgia rheumatica. Am Fam Physician.

2000, 1;61(7):2061-8, 2073.31. Dasgupta B, Dolan AL, Panayi GS, Fernndez L. An initially

double-blind controlled 96 week trial of depotmethylprednisolone against oral prednisolone in thetreatment of polymyalgia rheumatica. Br J Rheumatol.1998;37:18995.

32. Hodgkins P, Hull R. Diagnosing andmanaging polymyalgiarheumatica and temporal arteritis. Patients starting steroidsshould be given advice on risk of osteoporosis. BMJ.1997;315(7107):550.

33. Gabriel SE, Sunku J, Salvarani C, OFallon WM, Hunder GG.Adverse outcomes of anti-inflammatory therapy amongpatients with polymyalgia rheumatica. Arthritis Rheum.1997;40:18738.

34. Grossman JM, Gordon R, RanganathVK. American College ofRheumatology 2010 recommendations for the prevention andtreatment of glucocorticoid-induced osteoporosis. ArthritisCare Res (Hoboken). 2010;62:151526.

35. Weinstein RS. Clinical practice. Glucocorticoid-induced bonedisease. N Engl J Med. 2011;365:6270.

36. Dasgupta B, Matteson EL,Maradit-KremersH. Managementguidelines and outcome measures in polymyalgia rheumatic(PMR). Clin Exp Rheumatol. 2007;25:1306.

37. Spies CM, Burmester GR, Buttgereit F. Methotrexate treatmentin large vessel vasculitis and polymyalgia rheumatica. ClinExp Rheumatol. 2010;28:S1727.

38. Ferraccioli G, Salaffi F, de Vita S, Casatta L, Bartoli L.Methotrexate in polymyalgia rheumatica: preliminary resultsof an open randomized study. J Rheumatol. 1996;23:6248.

39. Caporali R, Cimmino MA, Ferraccioli G. Prednisolone plusmethotrexate for polymyalgia rheumatica: a randomized,double-blind placebo-controlled trial. Ann Intern Med.2004;141:493500.

40. Van der VeenMJ, DinantHJ, van-Vooma Frankort C,van-Albada-Kuipers GA, Bilsma JW. Canmethotrexate beused as a steroid sparing agent in the treatment ofpolymyalgia rheumatica and giant cell arteritis? Ann RheumDis. 1996;55:21823.

41. De Silva M, Hazleman BL. Azathioprine in giant cellarteritis/polymyalgia rheumatica: a double-blind study. AnnRheumDis. 1986;45:1368.

42. Salvarani C, Macchioni P, Manzini C. Infliximabplusprednisone or placebo plus prednisone for the initialtreatment of polymyalgia rheumatica: a randomized trial.Ann InternMed. 2007;146:6319.

43. HutchingsA, Hollywood J, Lamping DL. Clinical outcomes,quality of life, and diagnostic uncertainty in the first year ofpolymyalgia rheumatica. Arthritis Rheum. 2007;57:8039.

44. Salvarani C, Cantini F, Boiardi L, Hunder G. Polymyalgiarheumatica. Best Pract Res Clin Rheumatol. 2004;18:70522.

45. Kremers HM, Reinalda MS, Crowson CS, Zinsmeister AR,Hunder GG, Gabriel SE. Relapse in a population based cohortofpatients with polymyalgia rheumatica. J Rheumatol.2005;32:6573.

46. Salvarani C, Cantini F, Niccoli L. Acute-phase reactants andthe risk of relapse/recurrence in polymyalgia rheumatica: a

prospective follow up study. Arthritis Rheum. 2005;53:338.47. Roche NE, Fulbright JW, Wagner AD, Hunder GG, Goronzy JJ,

Weyand CM.Correlation of interleukin-6 production anddisease activity in polymyalgia rheumatica and giant cellarteritis. Arthritis Rheum. 1993;36:128694.

48. Kermani T, Warrington KJ. Polymyalgia rheumatica. Lancet.2013;381:6372.

49. Warrington KJ, Jarpa EP, Crowson CS. Increased risk ofperipheral arterial disease in polymyalgia rheumatica:a population-based cohort study. Arthritis Res Ther.2009;11:R50.

50. Salvarani C, Gabriel SE, OFallonWM,Hunder GG.Epidemiology of polymyalgia rheumatica in Olmsted County,Minnesota, 19701991. Arthritis Rheum. 1995;38:36973.

51. Gran JT, Myklebust G,Wilsgaard T, Jacobsen BK. Survival inpolymyalgia rheumatica and temporal arteritis: a study of 398cases andmatched population controls. Rheumatology(Oxford). 2001;40:123842.

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