Referencias Infecciones Hueso Articulacion Musculo PDF

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An Pediatr (Barc). 2015;83(3):216.e1---216.e10
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ASOCIACIÓN ESPAÑOLA DE PEDIATRÍA
Documento de Consenso SEIP-SERPE-SEOP sobre

etiopatogenia y diagnóstico de la osteomielitis aguda y
artritis séptica no complicadas
J. Saavedra-Lozano a,∗ , C. Calvo a,b , R. Huguet Carol c , C. Rodrigo a , E. Núñez a,b ,
C. Pérez a , R. Merino b , P. Rojo a , I. Obando a , F.J. Downey c , E. Colino a , J.J. García a ,
M.J. Cilleruelo a , F. Torner c y L. García a
a
Sociedad Española de Infectología Pediátrica (SEIP)
b
Sociedad Española de Reumatología Pediátrica (SERPE)
c
Sociedad Española de Ortopedia Pediátrica (SEOP)
Recibido el 8 de agosto de 2014; aceptado el 18 de agosto de 2014

Disponible en Internet el 11 de octubre de 2014
PALABRAS CLAVE Resumen Se presenta el Documento de Consenso sobre etiopatogenia y diagnóstico de la

Infección osteomielitis aguda y la artritis séptica no complicadas elaborado por la Sociedad Española de
osteoarticular; Infectología Pediátrica, la Sociedad Española de Reumatología Pediátrica y la Sociedad Española
Osteomielitis aguda; de Ortopedia Pediátrica.
Artritis séptica; En este documento se revisan la etiopatogenia y la fisiopatología de la infección osteoarticular
Etiología; aguda en niños, considerada como aquella no complicada, de origen comunitario, que presenta
Diagnóstico una evolución inferior a 14 días, así como la aproximación clínico-diagnóstica a estas entidades,
basándonos en las mejores evidencias científicas disponibles. En función de dichas evidencias,
se aportan una serie de recomendaciones para la práctica clínica.
© 2014 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. Todos los dere-
chos reservados.
KEYWORDS SEIP-SERPE-SEOP Consensus Document on aetiopathogenesis and diagnosis of

Osteoarticular uncomplicated acute osteomyelitis and septic arthritis
infection;
Acute osteomyelitis; Abstract This is a Consensus Document of the Sociedad Española de Infectología Pediátrica,
Septic arthritis; Sociedad Española de Reumatología Pediátrica and Sociedad Española de Ortopedia Pediátrica
Aetiology; on the aetiology and diagnosis of uncomplicated acute osteomyelitis and septic arthritis.
Diagnosis A review is presented of the aetiopathogenesis and pathophysiology of acute osteoarticular
infection defined as a process with less than 14 days of symptomatology, uncomplicated, and
community-acquired. The diagnostic approach to these conditions is summarised based on the
∗ Autor para correspondencia.
Correo electrónico: jesaave@yahoo.es (J. Saavedra-Lozano).
http://dx.doi.org/10.1016/j.anpedi.2014.08.006
1695-4033/© 2014 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. Todos los derechos reservados.
Documento descargado de http://www.analesdepediatria.org el 16/09/2015. Copia para uso personal, se prohíbe la transmisión de este documento por cualquier medio o formato.
216.e2 J. Saavedra-Lozano et al.
best available scientific knowledge. Based on this evidence, a number of recommendations for
clinical practice are provided.
© 2014 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reser-
ved.
Introducción Epidemiologia
La infección osteoarticular (IOA) presenta una especial Las IOA son más frecuentes en la infancia, con una preva-
importancia debido a que el sistema músculo-esquelético lencia en países desarrollados de 22 casos/100.000 niños2 . El
en el niño está en constante crecimiento. Así, una 50% de los casos se produce en < 5 años y, al menos, el 25% en
infección que afecte al cartílago de crecimiento o la epí- < 2 años3 . Se estima una incidencia anual de 4 casos/100.000
fisis puede producir una alteración en el desarrollo del niños de AS4 y de 2-13 casos/100.000 niños para la OmA5,6 ,
hueso, con las correspondientes secuelas. Las 3 socieda- siendo, esta última, hasta 2 veces más frecuente. En el caso
des participantes, la Sociedad Española de Infectología de osteomielitis neonatal, se describen de 1-3 casos/1.000
Pediátrica (SEIP), la Sociedad Española de Reumatología ingresos en cuidados intensivos7 . La relación varón:mujer es
Pediátrica (SERPE) y la Sociedad Española de Ortopedia de 1,2:3,7 veces7 .
Infantil (SEOP), consideramos muy importante la exis- Se ha descrito un aumento del número de casos de OmA
tencia de un documento de consenso que recoja la de hasta 2,8 veces en los últimos 20 años, manteniéndose
información científica publicada sobre la IOA no compli- constante el de AS5,6 , lo que podría deberse a la mejora
cada en pediatría. En este documento incluimos tanto la de las técnicas diagnósticas. Existe una serie de factores
osteomielitis aguda (OmA) como la artritis séptica (AS), predisponentes que favorecen el desarrollo de una IOA y que
revisándose, fundamentalmente, las infecciones comunita- se detallan en la tabla 2, aunque la mayoría de las IOA se
rias de causa hematógena y evolución clínica aguda (< 14 producen en niños sin enfermedad de base.
días). Además, se desarrolla un conjunto de recomenda- La OmA suele ser unifocal, afectando, generalmente, a
ciones, con nivel de evidencia y grado de recomendación las metáfisis de huesos largos, especialmente fémur (30%),
(tabla 1)1 . tibia (22%) y húmero (12%)7,8 , siendo menos frecuente la
Este consenso no pretende reemplazar el juicio clínico o afectación del calcáneo o la pelvis. La OmA pélvica se des-
establecer un protocolo para todos los niños con este tipo cribe entre el 1 y el 11% y suele afectar a niños mayores8,9 .
de infecciones y, probablemente, no representa el único Las infecciones multifocales son más frecuentes en recién
abordaje adecuado para la IOA en el niño. nacidos (RN) (hasta un 40%), niños con inmunodeficiencia
En otro documento posterior se abordará el tratamiento o en aquellos con enfermedad causada por Staphylococcus
de las IOA. aureus (S. aureus) resistente a meticilina (SARM)9,10 .
Tabla 2 Factores predisponentes que favorecen el desarro-

Tabla 1 Nivel de evidencia y fuerza de recomendación uti- llo de una infección osteoarticular
lizadas en este consenso Inmunodeficiencias primarias, como la enfermedad
Categoría Definición granulomatosa crónica, el síndrome de Wiskott-Aldrich o
el síndrome de Chediak-Higashi
Fuerza de la recomendación Infección por el virus de la inmunodeficiencia humana
A Buena evidencia Hemoglobinopatías, sobre todo, drepanocitosis
B Moderada evidencia Sepsis
C Pobre evidencia Traumatismos con bacteriemia (responsables del 30% de
Calidad de la evidencia casos de OmA)
I Estudios clínicos adecuadamente Varicela
aleatorizados Cirugía (articular, intestinal y urinaria)
II Estudios clínicos bien diseñados pero no Heridas penetrantes, infecciones cutáneas o presencia de
aleatorizados cuerpos extraños
Estudios de cohortes Hemodiálisis
Estudios de casos y controles Diabetes
Otros: múltiples series o consecuencia de Durante el periodo neonatal
resultados contundentes de experimentos Prematuridad
no controlados Infecciones cutáneas
III Opinión de expertos basada en experiencia Canalización umbilical o catéteres venosos centrales
clínica Infecciones previas, especialmente cuando asocian
Estudios descriptivos bacteriemia (o fungemia)
Recomendaciones de comités de expertos En ocasiones, se han desarrollado OmA tras la punción con
lanceta del talón
Modificado de Khan et al.1 .
Infecciones osteoarticulares 216.e3
Tabla 3 Etiología más frecuente de la infección osteoarticular en función de la edad y de los factores de riesgo asociados
Edad Bacterias
< 3 mesesa Staphylococcus aureus
Streptococcus agalactiae
Enterobacterias (especialmente Escherichia coli)
3 meses-5 añosb S. aureus
Kingella kingae
S. pyogenes
> 5 añosc S. aureus
S. pyogenes
Situación de riesgo Bacterias

Herida punzante en el pie con calzado deportivo Pseudomonas aeruginosa
Varicela y heridas S. pyogenes
Drepanocitosis Salmonella enteritidis
Déficit de complemento Neisseria meningitidisd
Recién nacido con patologías complejas, inmunodeficiencias, Staphylococcus plasmocoagulasa negativos; S.
pacientes con prótesis o material de osteosíntesis epidermidis, S. hominis, S. saprophyticus, S.
haemolyticus, S. lugdunensis. Candida spp., así como
otros cocos y bacilos grampositivos y bacilos
gramnegativos
Agammaglobulinemia Mycomplasma pneumoniae
Enfermedad granulomatosa crónica S. aureus, Serratia marcescens y Aspergillus fumigatus,
entre otros
Pacientes procedentes de países con alta endemia de tuberculosis, Mycobacterium tuberculosis
inmunodeficiencias que afectan al eje gamma
interferón-interleucina 12 y tratamientos con inmunomoduladores
biológicos que interfieren con la producción de interferón
a Otros microorganismos ocasionalmente asociados a infección osteoarticular en recién nacidos son: N. gonorrhoeae, Staphylococcus
plasmocoagulasa negativo o Candida.

b K. kingae puede producir infección osteoarticular en niños < 5 años, pero con mucha mayor frecuencia en aquellos < 2 años. Igualmente,
en < 2 años habría que considerar Streptococcus pneumoniae, y en niños mal vacunados < 5 años, Haemophilus influenzae.
c N. gonorrhoeae debe considerarse en adolescentes sexualmente activos.
d N. meningitidis puede producir artritis reactiva o por invasión directa en infecciones sistémicas.
En el caso de las AS, más del 90% son monoarticulares3 , son patógenos importantes Streptococcus agalactiae y las
siendo las articulaciones de miembros inferiores las más fre- enterobacterias (especialmente Escherichia coli). Entre los
cuentemente afectadas (70% de los casos): especialmente 3 meses y los 2-5 años, los agentes etiológicos más frecuen-
rodilla (35-40%), cadera (25-30%), tobillo (13-15%), codo tes son S. aureus y Kingella kingae, mientras que a partir de
(10%) y hombro (5%)3,4,11 . esa edad la gran mayoría de infecciones son producidas por
A nivel de la columna, la IOA puede ocasionar disci- S. aureus y, en menor medida, por Streptococcus pyogenes14
tis, más frecuentes en zona lumbar7,12,13 y en niños < 5 (tabla 3). En caso de artritis en adolescentes sexualmente
años, dado que el disco intervertebral se vasculariza desde activos, habría que pensar en Neisseria gonorrhoeae11 . Las
la vértebra adyacente (vascularización que desaparece bacterias asociadas a distintos factores de riesgo se detallan
posteriormente)7,8,12 . La discitis descrita en adolescentes en la tabla 3.
podría representar más una necrosis avascular que una ver-
dadera infección. Las vértebras se afectan en el 1-2% de los Patogenia
casos, especialmente en niños > 8 años.
Hasta en un 30% de niños (sobre todo neonatos [70% de Artritis séptica
los casos] y < 18 meses) coexisten OmA y AS (osteoartri-
tis), especialmente en hombro y cadera por la existencia de La mayoría de los casos de AS se producen a partir de
metáfisis intraarticular7,8,12 . la siembra hematógena de organismos en la sinovial. Las
endotoxinas bacterianas en el espacio articular inducen libe-
ración de citocinas, migración leucocitaria y destrucción de
Etiología la matriz del cartílago articular11 . En el caso de la cadera
y del hombro, a este efecto hay que unir la lesión produ-
Bacterias más frecuentes cida por el colapso vascular debido al aumento de la presión
intraarticular por acúmulo de pus.
El microorganismo más frecuente en todas las edades es La infección también puede llegar desde focos contiguos,
S. aureus. En RN y hasta los 3 meses de edad, también especialmente osteomielitis en lactantes13 . Finalmente,
las articulaciones pueden infectarse a partir de heri- la deambulación. Otros síntomas locales dependerán de la
das penetrantes, artroscopias o inyección intraarticular de localización:
medicamentos, las 2 últimas, excepcionalmente15 .
--- En la OmA, además de dolor, puede existir tumefacción,
Osteomielitis aguda calor e, incluso, eritema si la infección ha progre-
sado hasta el espacio subperióstico y el tejido celular
La forma más frecuente de infección es la vía hematógena. subcutáneo6 .
Menos frecuentes son las OmA producidas a partir de fractu- --- En las AS superficiales, como la rodilla, hay dolor, tume-
ras abiertas, heridas punzantes, mordeduras de animales o facción y calor, casi siempre sin eritema. Sin embargo,
infecciones contiguas como sinusitis, infecciones dentarias cuando la AS es profunda, como en la cadera, no hay
o mastoiditis. tumefacción, calor o rubor9 , y la sospecha clínica se
A partir de una bacteriemia, se produce la infección establece por el dolor referido en ingle, muslo o rodi-
de la metáfisis de huesos largos por su rico aporte vascu- lla ipsolaterales, junto con una limitación dolorosa de
lar: el lento flujo sanguíneo a través de sus asas capilares la movilidad de la articulación, especialmente con la
y la existencia de poros en el endotelio permiten el paso rotación interna: el niño suele presentar una actitud
de microorganismos. Las bacterias proliferan, formándose antiálgica de la cadera, manteniéndola en flexión, rota-
grandes colonias que obstruyen las luces capilares, dificul- ción externa y abducción.
tando la fagocitosis y la penetración de antibióticos. A partir --- Los pacientes con espondilodiscitis y sacroilitis evitan la
de los focos de infección metafisaria, se desarrolla infección deambulación y la sedestación, y mantienen la típica pos-
en la médula ósea y el hueso cortical. La existencia de vasos tura de trípode. Hace falta un alto índice de sospecha
transepifisarios en los RN y lactantes pequeños proporciona para el diagnóstico de la IOA en estas localizaciones9 .
una conexión vascular entre la metáfisis y la epífisis, favo-
reciendo la aparición de osteoartritis en estas edades. La
atrofia de los capilares metafisarios a los 18 meses hace que, Periodo neonatal
a partir de esta edad, la afectación articular sea excepcio-
nal, excepto en el caso de metáfisis intracapsulares, como La forma más benigna y frecuente cursa sin síntomas de
la cadera o el hombro13 . enfermedad sistémica ni fiebre, siendo la irritabilidad, la
S. aureus, patógeno más frecuente de las IOA, posee falta de apetito y la seudoparálisis del miembro afectado,
numerosas proteínas de superficie responsables de la adhe- junto con dolor a la movilización, el cuadro típico8 . Existe
rencia a los tejidos del huésped. Una vez lograda la un cuadro grave que asocia bacteriemia y signos típicos de
adherencia, la capacidad de formar biofilms o variantes de sepsis, siendo más característico en el RN pretérmino8,21 .
colonias pequeñas favorece la persistencia de la infección. También puede observarse OmA secundaria a cefalohema-
Además, es capaz de producir proteínas que inhiben la qui- toma o a la monitorización12 .
miotaxis, leucocidinas (leucocidina de Panton-Valentine o
PVL en inglés) que destruyen los leucocitos y modulinas con
capacidad lítica de los osteoblastos16,17 . Drepanocitosis
Manifestaciones clínicas Estos niños tienen un elevado riesgo de presentar OmA y

AS debido a oclusiones microvasculares11,22 . La presentación
Síntomas generales clínica de la OmA es similar a la de una crisis vaso-oclusiva
y el diagnóstico diferencial puede ser muy difícil. Los epi-
El inicio de los síntomas de una IOA aguda será de un periodo sodios infecciosos parecen cursar con fiebre más elevada,
< 14 días. Por encima de este tiempo se considera infec- dolor más persistente y en una única localización23 .
ción subaguda o crónica. Esta duración es arbitraria, aunque
generalmente aceptada, y otros criterios radiológicos, clí-
nicoa o anatomopatológicoas pueden ser importantes para Exploración física
definir mejor esta infección.
Los síntomas iniciales en la IOA pueden ser inespecíficos, La exploración física es clave para establecer la sospecha
como irritabilidad, malestar general, disminución del ape- diagnóstica y valorar la evolución posterior del cuadro clí-
tito o de la actividad. La fiebre no siempre está presente nico. Consta de:
en el momento de la consulta, sobre todo en RN y lactantes
pequeños6,9 , objetivándose en un 62-72% de los casos18 , y --- Exploración general minuciosa, comenzando por el lado
siendo más frecuente en la AS11,19 . contralateral.
--- Observación de la actitud espontánea.
Síntomas locales --- Evaluación del sistema músculo-esquelético, que puede
realizarse con el pGALS (pediatric Gait, Arms, Legs,
Lo más significativo es el dolor localizado y la disminución Spine), un instrumento validado y fácil de utilizar. De
de la movilidad o impotencia funcional, presentes en el forma simplificada se muestra en la tabla 4 24,25 .
56-95% y el 50-92% de las ocasiones, respectivamente6,20 , --- Comparación del lugar afectado con el contralateral sano,
con la adopción de una postura antiálgica. Cuando la infec- para distinguir diferencias de actitud, tamaño, tempera-
ción se sitúa en los miembros inferiores o el eje axial tura y color.
(espondilodiscitis, sacroilitis), aparece cojera o rechazo de --- Valoración de la deambulación.
Tabla 4 The pGALS (pediatric Gait, Arms, Legs, Spine), examen para la detección de síntomas músculo-esqueléticos
Preguntas
¿Tiene el niño dolor o rigidez (entumecimiento tras el reposo) en sus articulaciones, músculos o espalda?
¿Tiene dificultad para vestirse sin ayuda? (si antes lo hacía)
¿Tiene dificultad para subir o bajar escaleras? (si antes lo hacía)
Maniobras de detección ¿Qué valora?

Observar al paciente de pie y tumbado Actitud espontánea. Exantema. Dismetría. Tumefacción
articular. Desviación en valgo/varo. Atrofia muscular.
Pies planos
Miembros superiores
«Mantén las manos extendidas delante de ti» Flexión anterior de hombros
Extensión de codos, carpos y dedos
«Pon las palmas hacia arriba y cierra las manos en un Supinación de codos
puño» Flexión de las articulaciones de los dedos
«Haz pinza con el índice y el pulgar» Destreza manual
«Toca las yemas de los dedos con el pulgar de la Destreza manual
misma mano»
«Mantén juntas las palmas de las manos a la altura de Extensión de las articulaciones de dedos y carpos
los codos»
«Levanta los brazos, estíralos todo lo que puedas» Extensión de codos y muñecas
Abducción de hombros
«Pon las manos detrás del cuello» Abducción y rotación externa de hombros
Flexión de codos
Hay dolor al apretar los nudillos Articulaciones metacarpofalángicas
Miembros inferiores
Realizar signo de peloteo rotuliano Tumefacción de rodillas
«Extiende y flexiona las rodillas» Flexión y extensión de rodillas
Realizar movimientos pasivos de caderas Rotación, abducción y flexión de caderas
(Flexión pasiva de 90◦ de las rodillas y rotación
interna de la cadera en decúbito prono, es la
maniobra más sensible en la exploración de la cadera)
Realizar movimientos pasivos de tobillos Movilidad de articulaciones tibioastragalina y
subastragalina
Columna y temporomandibulares
«Abre mucho la boca»’ Articulaciones temporomandibulares y desviación de la
apertura bucal
«Mira al techo» Extensión de la columna cervical
«Intenta tocar el hombro con la oreja» Flexión lateral de la columna cervical
«De pie y con las rodillas extendidas, intenta tocar el Flexión de la columna toraco-lumbar
suelo» Escoliosis
Deambulación
Observar la marcha espontánea Cojera o rechazo de la deambulación
«Camina de puntillas»
«Camina de talones»
Modificado Goff et al.24 .
Para la exploración de la zona sacroilíaca puede ser de Diagnóstico de la infección osteoarticular

utilidad la maniobra tipo Fabere (http://www.aeped.es/
sites/default/files/documentos/cojera.pdf). Diagnóstico analítico y microbiológico
Conviene destacar que: 1) en la OmA es típico el dolor a la
presión a punta de dedo; 2) las maniobras exploratorias para La sospecha clínica, la anamnesis y la exploración física son
el diagnóstico de la sacroilitis, tipo Fabere, no son útiles en el primer paso hacia el diagnóstico. El resto de las pruebas
niños pequeños porque no colaboran bien, y 3) el eritema nos ayudarán a confirmarlo.
de la piel suprayacente a una articulación indica afectación
de tejidos blandos, no correspondiéndose, en la mayoría de --- Hemograma y reactantes de fase aguda: el aumento de la
los casos, con una verdadera artritis. velocidad de sedimentación globular (VSG), de la proteína
Tabla 5 Características del líquido articular

Normal Séptico Inflamatorio Traumático
Color Claro Turbio +/--- +/---
Leucocitos/mm3 < 200 > 50.000 2.000-50.000 < 2.000
Neutrófilos < 25% > 90% 50-80% 0-30%
Glucosa, mg/dl 80-100 < 20 20-50 > 50
Formación coágulo mucina Bueno Pobre Pobre Bueno
C reactiva (PCR) y de otros reactantes de fase aguda es --- Prueba de la tuberculina (o pruebas inmumológicas de
frecuente, aunque inespecífico. Estos valores no suelen diagnóstico): debería solicitarse ante la sospecha de
estar muy elevados, salvo en etapas evolucionadas. La tuberculosis osteoarticular, aunque suele cursar de una
combinación de PCR y VSG es de gran utilidad para la forma más subaguda o crónica.
valoración inicial, siendo improbable la existencia de una
IOA si no se elevan los primeros días del ingreso26 . La El diagnóstico de otras causas infecciosas menos fre-
leucocitosis es poco frecuente19 . cuentes podría requerir la realización de otras pruebas
--- Hemocultivo: debe recogerse siempre para intentar la específicas (RCP, serologías, etc.).
identificación del microorganismo responsable, aunque su
rentabilidad es < 50%27 . Pruebas de imagen
--- Análisis del líquido articular: la artrocentesis o punción
del espacio articular para la extracción de líquido sino- --- Radiografía (Rx) simple. La Rx simple continúa teniendo
vial debería realizarse ante toda sospecha de AS, previo un papel relevante ante la sospecha de una IOA, siendo
al inicio del tratamiento antibiótico. Así, el análisis cito- útil para descartar otras patologías, como fracturas o
bioquímico del líquido sinovial, aunque inespecífico, nos tumores. En la OmA suele ser normal en los primeros 10-14
puede ofrecer una aproximación diagnóstica (tabla 5)15 . días, alcanzando una sensibilidad y especificidad de hasta
Generalmente, un recuento > 50.000 células/mm3 con el 82 y el 92%, respectivamente, a las 2-3 semanas del
predominio de polimorfonucleares es más indicativo de comienzo del cuadro clínico. Son imágenes características
etiología infecciosa, como lo es una disminución de la la osteólisis, la osteopenia y la elevación o engrosamiento
glucosa (< 50% de la plasmática). perióstico36 . En la osteomielitis vertebral o espondilo-
La identificación del patógeno responsable es el gold discitis puede observarse una disminución del espacio
standard del diagnóstico de la AS, aunque solo se logra intervertebral o erosiones vertebrales en la Rx lateral7 .
en un 20-80% de los casos6,28 . Es ideal enviar, lo antes En el caso de la AS, puede objetivarse un aumento del
posible, todo el líquido o material obtenido en un tubo espacio articular y de partes blandas en la fase aguda.
estéril (evitar torundas) para que sea procesado para tin- --- Ecografía. Técnica de gran utilidad en la AS, por ser
ción de Gram y cultivo. La recogida del líquido articular barata, de fácil acceso y por su elevada sensibilidad.
en frasco de hemocultivo aumenta la rentabilidad del Detecta derrame articular en el 95% de los casos, aun-
aislamiento, en especial ante la sospecha de K. kingae que las características ecográficas no son patognomónicas
(posiblemente el agente más frecuente cuando los culti- de infección. Es especialmente importante en el diag-
vos son negativos)7,29 . La técnica de reacción en cadena nóstico de AS de cadera y hombro dada la dificultad del
de polimerasa (RCP) permite identificar esta y otras bac- diagnóstico clínico6,11 , y puede ser de gran ayuda para
terias con mal crecimiento en cultivo o en infecciones guiar la realización de artrocentesis. La técnica Doppler
previamente tratadas con antibiótico6,14,30-32 . puede documentar un aumento del flujo vascular, aunque
No se han encontrado, hasta la fecha, unas caracterís- su ausencia no descarta una AS.
ticas biológicas y clínicas de las AS que permitan predecir --- En las OmA, es útil para poner de manifiesto abscesos sub-
el patógeno involucrado33,34 , salvo la menor edad, menor periósticos o de partes blandas, pero su normalidad no
repercusión clínica y de marcadores inflamatorios de los excluye esta infección6,7,37 . Igualmente, puede ser utili-
niños con infección por Kingella19,32,34 . dad para la punción ósea guiada. En fases precoces, la
Para el diagnóstico de la artritis tuberculosa conviene presencia de Doppler positivo a nivel óseo orienta hacia
recoger una muestra adicional para tinción de Ziehl- la presencia de OmA.
Neelsen, cultivo y RCP, pudiendo requerir una biopsia --- Tomografía computarizada (TC). Aunque no detecta cam-
sinovial para el diagnóstico35 . bios específicos de forma precoz, puede objetivar edema
--- Punción ósea: algunos autores no la consideran necesaria de partes blandas y abscesos profundos extraóseos,
previamente a la instauración del tratamiento antibió- pudiendo facilitar la punción-drenaje. Puede resultar útil
tico empírico en la OmA, reservándola para los casos para el diagnóstico de localizaciones pélvicas o de for-
con mala evolución, presencia de abscesos u osteomie- mas subagudas/crónicas de infección, pudiendo detectar
litis crónicas6,19 . Sin embargo, algunos centros la realizan secuestros óseos7 . En la actualidad, no suele realizarse
habitualmente sin complicaciones, con/sin ecografía, por su excesiva radiación.
permitiendo la identificación del microorganismo hasta --- Resonancia magnética. Es, probablemente, la mejor
en un 40-60% de los casos7 . prueba de imagen para el diagnóstico de OmA, y resulta
Sospecha infección osteoarticular
Hemograma+PCR+VSG
hemocultivo
Rx simple + ecografía ósea y articularc
Sospecha artritis séptica Sospecha osteomielitis
RM Si no disponibilidad
Artrocentesisa de RM o sospecha
de OM multifocal
Si absceso
Si evolución tórpida
o complicada Gammagrafía
Punción-drenajeb ósea
RM
Figura 1 Algoritmo diagnóstico de la infección osteoarticular.

a
En la artritis séptica de cadera y hombro debe considerarse la realización de descompresión articular lo antes posible (véase el
texto).
b
La punción-drenaje se podrá realizar guiada por ecografía o tomografía computarizada.
c
La ecografía es muy útil para la orientación diagnóstica inicial de la artritis séptica, pero no tanto de la osteomielitis (véase el
texto).
de gran utilidad en el estudio de lesiones del esqueleto --- Otras técnicas. La TC por emisión de fotón único o la gam-
axial y de la pelvis7,12 . Si conocemos la localización de magrafía de médula con sulfuro coloidal podrían, en un
la lesión, tiene una alta sensibilidad (97%) y especifici- futuro, tener indicaciones en esta patología.
dad (92%)7 . No obstante, puede presentar dificultad para
diferenciar otras lesiones que cursan con edema tisular, Aunque, en la mayoría de las situaciones, el diagnóstico
como tumores, fracturas, infartos o cambios tras contu- de OmA debería confirmarse con una prueba de imagen más
sión, aunque en la práctica clínica no suele existir este allá de la Rx simple, en formas clínicas leves, con buena
problema diagnóstico. Su coste, la necesidad de seda- respuesta al tratamiento, estas podrían no ser necesarias.
ción en niños pequeños y la menor disponibilidad hacen En la figura 1 se muestra un algoritmo para el diagnóstico
que, con frecuencia, su uso quede restringido a casos con de la IOA.
evolución tórpida o complicada. Sus principales indicacio-
nes, serían: confirmación de osteomielitis, sospecha de
Diagnóstico diferencial
complicaciones (absceso/secuestro), osteomielitis verte-
bral o pélvica, ecografía o gammagrafía no concluyentes
de IOA y AS con falta de respuesta al tratamiento Diagnóstico diferencial de artritis séptica
antibiótico.
--- Gammagrafía ósea. A pesar de su escasa especificidad, En la tabla 6 se muestran las patologías más relevantes
es una técnica muy sensible para localizar osteomieli- a diferenciar con la AS monoarticular, así como caracte-
tis, sacroilitis o espondilodiscitis, así como para descartar rísticas específicas importantes25 . La infección de piel y
multifocalidad. Se ha encontrado una sensibilidad menor partes blandas o la bursitis de rodilla también deben ser
en lactantes pequeños o neonatos, y en bacterias muy consideradas. En raras ocasiones, la AS será poliarticular,
virulentas como SARM de la comunidad (AC)7,38 . Por su precisando diferenciarla de enfermedades reumatológicas,
facilidad y rapidez, se prefiere como isótopo el tecnecio- como lupus eritematoso sistémico, fiebre reumática o artri-
99, pero puede dar falsos positivos en otras enfermedades tis idiopática juvenil, así como de artritis reactivas de
con hiperactividad osteoclástica como fracturas, tumo- algunas infecciones11 (tabla 7).
res, infartos óseos o lesiones posquirúrgicas37,39 . El
galio-67 o los leucocitos marcados se consideran más Diagnóstico diferencial de osteomielitis aguda
específicos de cuadro infeccioso activo, pero son técni-
cas más complejas, requiriendo hasta 48 h para obtener El diagnóstico diferencial se plantea con: 1) celulitis e
las imágenes39 . infecciones de partes blandas, especialmente miositis (a
Tabla 6 Diagnóstico diferencial de monoartritis

Edad Sexo Líquido sinovial Datos clave
(años)
Aspecto Recuento Cultivo o
(células/mm3 ) RCP
Artritis séptica <5 V Turbio, > 50.000 (+) Inmovilidad por dolor,
purulento afectación del estado general,
comienzo agudo
Artritis vírica Amarillo, < 10.000 (---) Generalmente, poliarticular
transparente Exantema, leucopenia
Serología (+)
Artritis Amarillo, > 10.000 (---) Generalmente, poliarticular
postinfecciosaa turbio Antecedente de faringitis o
diarrea
AIJ (oligoarticular) <6 M Amarillo, > 10.000 (---) Artritis persistente. ANA (+)
turbio
AIJ. ArE >6 V Amarillo, > 10.000 (---) Artritis persistente y/o
turbio entesitis
HLA B27 (+)
Trastorno de Hemático (---) Hematomas en lugares poco
coagulación habituales
Artritis Amarillo, 10-20.000 (+) Mantoux (+). Rx tórax +/---.
tuberculosa turbio Ambiente epidemiológico
Sinovitis Hemático (---) Proliferación benigna de
villonodular sinovialb
Diagnóstico por biopsia
Hemangioma Hemático (---) Proliferación benigna de vasos
sinovial sinoviales. Diagnóstico por RM
Artritis traumática > 10 Amarillo o < 2.000 (---) Traumatismo/aumento
hemático actividad
Sinovitis 3-9 V Artrocentesis El cuadro clínico permite
transitoria no indicada sospecharla
cadera Puede existir antecedente de
infección viral autolimitada
Resolución en 5-7 días
Poco frecuente en < 3 años
Enfermedad de 3-9 V Artrocentesis El cuadro clínico permite
Perthes no indicada sospecharla
Antecedente de episodios de
cojera
Prueba de imagen compatible
AIJ: artritis idiopática juvenil; ANA: anticuerpos antinucleares; ArE: artritis relacionada con entesitis; M: mujer; RM: resonancia magné-
tica; RCP: reacción de la polimerasa en cadena; V: varón.
a Bacterias más frecuentemente implicadas son: S. pyogenes, Salmonella, N. meningitidis y N. gonorrhoeae.
b Algunos tumores óseos metafisarios y epifisarios, como el sarcoma de Ewing, pueden invadir la articulación y ocasionar derrame articular.
veces asociadas a OmA); 2) fracturas y otras lesiones trau- linfoproliferativa, cuya sintomatología de dolor e inflama-
máticas; 3) osteocondrosis, que suelen cursar con signos ción podría confundirse con una OmA8,12 , y 9) osteonecrosis
inflamatorios locales, sin aumento de reactantes de fase por crisis vasooclusivas en la enfermedad de células
aguda y con imagen radiológica típica; 4) tumores benignos falciformes8,22 . En los infrecuentes casos de localización
(osteoma osteoide, osteoblastoma); 5) tumores malignos, múltiple (S. aureus, Bartonella, Coxiella), es necesario rea-
como el sarcoma de Ewing (afectación de partes blandas, lizar diagnóstico diferencial con OCRM.
fiebre y afectación del estado general), el neuroblastoma La biopsia ósea y el estudio histológico deberían rea-
(metástasis en hueso) y el osteosarcoma; 6) osteítis inflama- lizarse cuando el diagnóstico sea dudoso, precisando el
torias asépticas, como la osteomielitis crónica recurrente procesamiento para cultivo y determinación de RCP de
multifocal (OCRM); 7) histiocitosis de células de Langer- microorganismos menos frecuentes, como hongos y mico-
hans, que puede cursar clínica y radiológicamente de bacterias. En la tabla 7 se exponen las recomendaciones más
forma indistinguible de la osteomielitis; 8) enfermedad relevantes de este consenso con el grado de evidencia.
Tabla 7 Resumen de recomendaciones y evidencia

--- La OmA y la AS son más frecuentes en menores de 5 años (AI)
--- El 70% de los casos afecta a los miembros inferiores, generalmente en una única localización (AI)
--- El microorganismo más frecuentemente aislado en todas las edades es S. aureus (AI). En RN y hasta los 3 meses de edad,
son también patógenos importantes S. agalactiae y las enterobacterias (sobre todo E. coli) (AI)
--- K. kingae es frecuente, sobre todo, en niños entre 3 meses y 5 años de edad, donde es la segunda causa etiológica (AI)
--- La AS por Salmonella puede ocurrir, rara vez, en niños sanos, pero es más característica de niños inmunodeprimidos y,
especialmente, con hemoglobinopatías, como drepanocitosis. La duración del tratamiento debería ser, al menos, de 4-6
semanas (BIII)
--- La fiebre o febrícula pueden no estar presentes en el momento de la consulta. El síntoma más significativo es el dolor,
responsable de la inmovilidad del lugar afectado (AII)
--- El diagnóstico de las IOA es fundamentalmente clínico, siendo clave el examen físico, apoyándose en los marcadores de
inflamación y de imagen y el análisis del líquido sinovial en las AS (AII)
--- El examen citobioquímico del líquido articular es importante para el diagnóstico de AS, aunque tampoco es específico (BIII)
--- El diagnóstico definitivo se establece cuando los cultivos (líquido articular, sangre, material óseo) o la RCP son positivos
(AI). En el caso de que las pruebas microbiólogicas fueran negativas, el diagnóstico es solo de presunción
--- En la AS siempre debería realizarse artrocentesis para el diagnóstico y la descompresión del espacio articular (AI). En caso
de AS evolucionadas o material más organizado, podría requerir apertura quirúrgica para el drenaje y la obtención de
muestras (BII)
--- Aunque es una práctica habitual en algunos centros que puede ayudar al abordaje de la OmA al aumentar la rentabilidad
diagnóstica, la obtención de una muestra ósea para el diagnóstico microbiológico previo al inicio de antibioterapia no es
imprescindible para el abordaje de la OmA hematógena no complicada (AII); no obstante, debería valorarse ante la falta de
respuesta a la antibioterapia a las 48-72 h del inicio de la misma (BII) y en la OmA no hematógena
--- Se debe realizar una Rx simple inicial de la zona supuestamente afectada por su disponibilidad, bajo coste y la posibilidad
de detectar otras patologías subyacentes o cambios crónicos en controles evolutivos (AII)
--- La ecografía es la técnica más útil en la valoración inicial de la AS por su elevada sensibilidad para la detección de aumento
de líquido articular, aunque las características del derrame articular no son específicas (AII)
--- Si sospechamos una OmA, la radiología es negativa y no se localiza clínicamente la lesión, se debería realizar una
gammagrafía ósea (AII), especialmente ante sospecha de afectación del esqueleto axial y huesos pequeños
--- La RM constituye la prueba de imagen más específica en las IOA, especialmente en la OmA (AI), pudiendo ser muy útil para
descartar o confirmar IOA en caso de dudas en el diagnóstico. En el caso de AS no suele ser necesaria. En las OmA, aunque
no tiene por qué realizarse en todas las situaciones, puede ser de mucha utilidad, especialmente en caso de afectación de
esqueleto axial, evolución tórpida o sospecha de complicaciones (AII)
Conflicto de intereses 5. Gafur OA, Copley LA, Hollmig ST, Browne RH, Thornton
LA, Crawford SE. The impact of the current epidemio-
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The n e w e ng l a n d j o u r na l of m e dic i n e
Review Article
Dan L. Longo, M.D., Editor
Inflammatory Muscle Diseases

Marinos C. Dalakas, M.D.
I
From the Department of Neurology, nflammatory myopathies are the largest group of potentially
Neuromuscular Division, Thomas Jeffer- treatable myopathies in children and adults. They constitute a heterogeneous
son University, Philadelphia; and Neuro-
immunology Unit, University of Athens group of disorders that are best classified, on the basis of distinct clinicopatho-
Medical School, Athens. Address reprint logic features, in four subtypes: dermatomyositis, polymyositis, necrotizing auto-
requests to Dr. Dalakas at the Depart- immune myositis, and inclusion-body myositis (throughout this review, I use this
ment of Neurology, Neuromuscular Divi-
sion, Thomas Jefferson University, 901 term to refer specifically to sporadic inclusion-body myositis).1-6 A fifth subtype,
Walnut St., Philadelphia, PA 19107, or at termed overlap myositis, is also beginning to be recognized. The identification of
marinos.dalakas@jefferson.edu. the correct subtype and the distinction of these conditions from other diseases
N Engl J Med 2015;372:1734-47. that have characteristics that mimic these conditions is fundamental, because each
DOI: 10.1056/NEJMra1402225 subtype has a different prognosis and response to therapies. This review reflects
Copyright © 2015 Massachusetts Medical Society.
the current knowledge of these conditions, highlights how best to avoid erroneous
diagnoses, describes the main clinicopathologic and immunologic features, and pro-
vides practical guidelines regarding therapies.
Gener a l Cl inic a l Fe at ur e s
Patients with inflammatory myopathies have increasing difficulty with tasks re-
quiring the use of proximal muscles, such as getting up from a chair, climbing steps,
or lifting objects.1-6 Tasks requiring distal muscles, such as buttoning or holding
objects, are affected early in inclusion-body myositis but only in advanced cases of
polymyositis, dermatomyositis, and necrotizing autoimmune myositis. The ocular
muscles are spared in all subtypes, but facial muscles are commonly affected in
inclusion-body myositis.3 In all disease subtypes, neck-extensor and pharyngeal
muscles can be involved, which results in difficulty holding up the head (head drop)
or in dysphagia. In advanced and rare acute cases, the respiratory muscles can be
affected. Muscle atrophy is detected early in inclusion-body myositis, with selective
atrophy of the quadriceps and forearm muscles, but it develops in all subtypes if
the weakness is severe and chronic. Myalgia and muscle tenderness may occur,
especially in patients with the antisynthetase syndrome (see the Glossary),6,7 but if
pain is severe and the weakness follows a “breakaway” pattern, in which the pa-
tient has difficulty sustaining effort, fasciitis or fibromyalgia should be ruled out.
Extramuscular manifestations may occur in all inflammatory myopathies, al-
though they occur in inclusion-body myositis only in rare cases; these manifesta-
tions include systemic symptoms, such as fever, arthralgia, and Raynaud’s phe-
nomenon, as seen in the antisynthetase syndrome4,6,7; cardiac arrhythmias or
ventricular dysfunction, in relatively uncommon cases in which the affected car-
diac muscle is clinically symptomatic; and pulmonary complications, due primar-
ily to interstitial lung disease, which are reported in 10 to 40% of patients.8 The
prevalence of interstitial lung disease, a condition that is best detected with high-
resolution computed tomography, is as high as 70% among patients with anti–his-
tidyl–transfer RNA (tRNA) synthetase (anti-Jo-1) or anti–melanoma differentiation–
1734 n engl j med 372;18 nejm.org April 30, 2015
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Copyright © 2015 Massachusetts Medical Society. All rights reserved.
Glossary
Anti–cytosolic 5′-nucleotidase 1A (anti-cN1A, or anti-NT5C1A): Autoantibody directed against the cN1A nuclear protein
involved in RNA processing; associated with inclusion-body myositis.
Anti–histidyl–transfer RNA synthetase (anti-Jo-1): The most common autoantibody associated with the antisynthetase
syndrome, which consists of myopathy, fever, interstitial lung disease, Raynaud’s phenomenon, arthritis, and “me-
chanic’s hands.”
Anti–3-hydroxy-3-methylglutaryl–coenzyme A reductase (anti-HMGCR): Autoantibody directed against HMGCR, the
pharmacologic target of statins; specific for necrotizing autoimmune myositis.
Anti–melanoma differentiation–associated protein-5 (anti-MDA-5): Autoantibody directed against a cytoplasmic RNA-
specific helicase; associated with amyopathic dermatomyositis or rapidly progressive interstitial lung disease.
Anti-Mi-2: Autoantibody directed against a nuclear DNA helicase involved in transcriptional activation; associated with
typical skin lesions of dermatomyositis.
Anti–signal recognition particle (anti-SRP): Autoantibody directed against a polypeptide complex involved in protein
transport to endoplasmic reticulum; specific for necrotizing autoimmune myositis.
Anti–transcriptional intermediary factor 1 γ (anti-TIF-1γ): Autoantibody involved in cell growth and differentiation; seen
in cancer-associated dermatomyositis, along with anti–nuclear matrix protein 2 (anti-NXP-2).
associated protein (MDA)–5 antibodies (see the bined with a red flush on the face, fatigue, and
Glossary).6-8 a reluctance to socialize.2,3
The symptoms of dermatomyositis may over-
lap with those of systemic sclerosis and mixed
Specific Cl inic a l Fe at ur e s
connective-tissue disease1-7; in such cases, the typi-
Dermatomyositis cal skin rash is transient or faint. Overlap myo-
The specific clinical features of inflammatory sitis is now starting to be recognized as a dis-
myopathies are described in Table 1 and in the tinct entity; it manifests without the rash that is
Supplementary Appendix, available with the full typical of dermatomyositis, with prominent patho-
text of this article at NEJM.org. Dermatomyositis logic changes in the perifascicular, interfascicular,
is seen in both children and adults, and the early and perimysial regions, and is frequently associ-
symptoms include distinct skin manifestations ated with antisynthetase antibodies.10 In adults,
accompanying or preceding muscle weakness; the the risk of cancer is increased during the first
skin manifestations include periorbital heliotrope 3 to 5 years after the onset of dermatomyositis,
(blue–purple) rash with edema; erythematous rash with reported a frequency of 9 to 32%.11,12 The
on the face, knees, elbows, malleoli, neck, anterior most common cancers are ovarian cancer, breast
chest (in a V-sign), and back and shoulders (in a cancer, colon cancer, melanoma, nasopharyngeal
shawl sign); and a violaceous eruption (Gottron’s cancer (in Asians), and non-Hodgkin’s lymphoma;
rash) on the knuckles, which may evolve into a the risk of these cancers necessitates a thorough
scaling discoloration.1-7,9 The lesions are photo- annual workup in the first 3 years after disease
sensitive and may be aggravated by ultraviolet onset.11,12
radiation.6,7,9 Dilated capillary loops at the base
of the fingernails, irregular and thickened cuti- Polymyositis
cles, and cracked palmar fingertips (“mechanic’s Polymyositis is rare as a stand-alone entity and
hands”) are characteristic of dermatomyositis.1-3 is often misdiagnosed; most patients whose con-
Subcutaneous calcifications, sometimes extrud- dition has been diagnosed as polymyositis have
ing to the surface of the skin and causing ulcer- inclusion-body myositis, necrotizing autoimmune
ations and infections, may occur and are espe- myositis, or inflammatory dystrophy.3,13 Polymyo-
cially common among children. If the patient’s sitis remains a diagnosis of exclusion and is best
strength appears to be normal, the dermatomyo- defined as a subacute proximal myopathy in adults
sitis may be limited to the skin (amyopathic der- who do not have rash, a family history of neuro-
matomyositis),9 although subclinical muscle in- muscular disease, exposure to myotoxic drugs
volvement is frequent.1-3 In children, an early (e.g., statins, penicillamine, and zidovudine), in-
symptom is “misery,” defined as irritability com- volvement of facial and extraocular muscles, en-
n engl j med 372;18 nejm.org April 30, 2015 1735

1736
Table 1. Criteria Supporting the Diagnosis of Inflammatory Myopathies.
Criterion Dermatomyositis Polymyositis Necrotizing Autoimmune Myositis Inclusion-Body Myositis

Pattern of muscle Subacute onset of proximal symmetric Subacute onset of proximal symmetric Acute or subacute onset of proxi- Slow onset of proximal and distal weak-
weakness weakness with characteristic skin weakness in adults (diagnosis is mal, often severe weakness in ness; atrophy of quadriceps and
rash in patients of any age made when other causes have been adults forearms; frequent falls; mild facial
ruled out)* muscle weakness in people older
than 50 years of age
Creatine kinase level High, up to 50 times the upper limit of High, up to 50 times the upper limit of Very high; more than 50 times the Up to 10 times the upper limit of nor-
normal; can at times be normal normal in early active disease; may upper limit of normal in early mal; can be normal or slightly
linger at up to 10 times the upper active disease elevated
The
limit of normal
Electromyography Myopathic units (active and chronic) Myopathic units (active and chronic) Active myopathic units Myopathic units (active and chronic)
with some mixed large-size poten-
tials
Muscle biopsy Perivascular, perimysial, and perifascic- CD8+ cells invading healthy fibers; wide- Scattered necrotic fibers with mac- CD8+ cells invading healthy fibers;
ular inflammation; necrotic fibers in spread expression of MHC class I rophages; no CD8+ cells or vac- widespread expression of MHC
“wedge-like” infarcts; perifascicular antigen; no vacuoles; ruling out of uoles; deposits of complement class I antigen; autophagic vacu-
atrophy; reduced capillaries† inflammatory dystrophies on capillaries‡ oles,§ ragged-red or ragged-blue
fibers; congophilic amyloid depos-
its¶
Autoantibodies Anti-MDA-5, anti-Mi-2; anti-TIF-1 and Antisynthetase antibodies (often seen in Anti-SRP and anti-HMGCR, specif- Anti-cN1A (of uncertain pathologic sig-
anti-NXP-2 (implicated in cancer- overlap myositis) associated with inic for necrotizing autoimmune nificance)
n e w e ng l a n d j o u r na l

associated dermatomyositis) terstitial lung disease, arthritis, myositis
of
fever, and “mechanic’s hands”

Magnetic resonance May show active inflammation May show active inflammation; could May show active inflammation; Shows selective muscle involvement,
imaging guide biopsy site could guide biopsy site but might be difficult to distinguish
n engl j med 372;18 nejm.org April 30, 2015

atrophy from chronic inflammation

m e dic i n e
* Drug-induced myopathies (e.g., penicillamine, statins, or antiretrovirals), inflammatory dystrophies (such as those due to mutations in the genes encoding dysferlin, calpain, or anocta-
min; Becker’s muscular dystrophy; facioscapulohumeral muscular dystrophy; or myofibrillar myopathies), inclusion-body myositis, necrotizing autoimmune myositis, metabolic myopa-
thies, and fasciitis or fibromyalgia need to be ruled out.
† Similar pathologic changes in the perifascicular, perimysial, and interfascicular areas (to a lesser degree of severity) can be seen in overlap myositis (without skin lesions) or the antisyn-
thetase syndrome.
‡ Metabolic muscle diseases presenting as myoglobinuria and toxic or drug-induced myopathies need to be ruled out.
§ In clinical inclusion-body myositis, when patients have the typical inclusion-body myositis phenotype, vacuoles are absent; such patients are erroneously thought to have polymyositis
because of polymyositis-like inflammation; ragged-red fibers or cytochrome oxidase–negative fibers are frequently present and are helpful in diagnosis.
¶ TDP43 and p62 deposits, detected with the use of immunostaining, have been proposed as tissue biomarkers.
docrinopathy, or the clinical phenotype of inclu- quadriceps muscles; frequent falls due to quad-
sion-body myositis.1-3 riceps muscle weakness causing buckling of the
knees; and mild facial-muscle weakness.1-5,20-23 The
Necrotizing Autoimmune Myositis axial muscles may be affected, which results in
Necrotizing autoimmune myositis is a distinct camptocormia (bending forward of the spine) or
clinicopathologic entity that occurs more frequent- head drop. Dysphagia occurs in more than 50%
ly than polymyositis, accounting for up to 19% of the patients.23
of all inflammatory myopathies.13 It can occur at
any age but is seen primarily in adults; it starts Di agnosis
either acutely, reaching its peak over a period of
days or weeks, or subacutely, progressing steadi- The diagnosis of the exact subtype of inflamma-
ly and causing severe weakness and very high tory myopathy is based on the combination of
creatine kinase levels.14,15 Necrotizing autoimmune clinical history, tempo of disease progression,
myositis occurs alone or after viral infections, in pattern of muscle involvement, muscle enzyme
association with cancer, in patients with connec- levels, electromyographic findings, muscle-biopsy
tive-tissue disorders such as scleroderma, or in analysis, and for some conditions, the presence
patients taking statins, in whom the myopathy of certain autoantibodies (Table 1). Typical skin
continues to worsen after statin withdrawal (if changes, with or without muscle weakness, indi-
the myopathy improves within 4 to 6 weeks after cate dermatomyositis; a subacute onset of proxi-
discontinuation of statins, it was probably caused mal myopathic weakness points to polymyositis
by toxic effects of the drug rather than by im- or necrotizing autoimmune myositis; and slowly
mune myopathy).3,4,6,14-16 Most patients with nec- progressive proximal and distal weakness with
rotizing autoimmune myositis have antibodies selective atrophy points to inclusion-body myosi-
against signal recognition particle (SRP) or against tis. Electromyography is diagnostically useful in
3-hydroxy-3-methylglutaryl–coenzyme A reductase all disease subtypes to rule out neurogenic con-
(HMGCR) (see the Glossary).14-16 ditions and assess disease activity. Serum creatine
kinase is elevated in all subtypes, but very high
Inclusion-Body Myositis levels from the outset point to necrotizing auto-
Inclusion-body myositis is the most common and immune myositis. Magnetic resonance imaging
disabling inflammatory myopathy among persons (MRI) is helpful for diagnosis when muscle edema
50 years of age or older.1-5,17-23 Its prevalence, is present or myofasciitis is suspected, as well as
which was initially estimated in the Netherlands for identification of the particular muscles affected
as 4.9 cases per million population,18 is much by atrophy in inclusion-body myositis. Muscle
higher when adjusted for age; in two later stud- biopsy is essential for the diagnosis of polymyo-
ies in Australia and the United States, the age- sitis, overlap myositis, necrotizing autoimmune
adjusted prevalence ranged from 51.3 to 70 cases myositis, and inclusion-body myositis, as well as
per million.19,22 In a small chart-review study con- for ruling out disease mimics such as dystrophies
ducted in one U.S. county, the estimated inci- or metabolic or vacuolar myopathies. Assessment
dence of inclusion-body myositis was 7.9 cases of autoantibodies is helpful for the diagnosis of
per million in the 1980s and 1990s.19 The dis- necrotizing autoimmune myositis and for the
ease starts insidiously and develops over a peri- classification of distinct subtypes and their as-
od of years, at times asymmetrically (i.e., it may sociations with systemic organ involvement, such
start or be more severe in one extremity or on one as interstitial lung disease.
side of the body), and progresses steadily, simu- Among muscle-derived enzymes in serum, the
lating a late-life muscular dystrophy or slowly most sensitive indicator of inflammatory myop-
progressive motor-neuron disease.1-5 Although in- athy is creatine kinase, which is elevated in pa-
clusion-body myositis is commonly suspected tients with active disease. The highest levels, up to
when a patient’s presumed polymyositis does not more than 50 times the upper limit of normal,
respond to therapy,3 features that can lead to an are seen in patients with necrotizing autoimmune
early clinical diagnosis include the early involve- myositis, and the lowest (less than 10 times the
ment of distal muscles, especially foot extensors upper limit of normal) are seen in patients with
and finger flexors; atrophy of the forearms and inclusion-body myositis. Although serum levels

of creatine kinase usually parallel disease activ- Figure 1 (facing page). Dermatomyositis: A Comple-
ity, they can be normal or only slightly elevated ment-Mediated Microangiopathy.
in patients with active dermatomyositis, overlap Panel A shows a cross-section of a hematoxylin and
myositis, or active inclusion-body myositis. Along eosin–stained muscle-biopsy sample with classic der-
with creatine kinase, aspartate aminotransferase matomyositis perifascicular atrophy (layers of atrophic
and alanine aminotransferase levels are also el- fibers at the periphery of the fascicle [arrows]) and
some inflammatory infiltrates. Panel B shows the de-
evated, a sign that is sometimes erroneously in- position of complement (membranolytic attack com-
terpreted as indicating liver disease and that leads plex, in green) on the endothelial cell wall of endo-
to an investigation with a liver biopsy instead of mysial vessels (stained in red with Ulex europaeus
a muscle biopsy. Serum aldolase levels may be lectin), which leads to destruction of endothelial cells
also elevated, especially if the fascia is involved. (shown in orange, indicating the superimposition of
red and green). Consequently, in the muscles of pa-
Electromyography can show myopathic motor- tients with dermatomyositis (shown in Panel C), as
unit potentials (short-duration, low-amplitude compared with a myopathic control (Panel D), the den-
polyphasic units on voluntary activation) and in- sity of the endomysial capillaries (in yellow–red) is re-
creased spontaneous activity with fibrillations, duced, especially at the periphery of the fascicle, with
complex repetitive discharges, and positive sharp the lumen of the remaining capillaries dilated in an ef-
fort to compensate for the ischemic process.1,2 Panel E
waves. These findings are useful in determining shows a schematic diagram of a proposed immuno-
whether the myopathy is active or chronic and in pathogenesis of dermatomyositis. Activation of com-
ruling out neurogenic disorders, but they cannot plement component 3 (C3) (probably triggered by anti-
be used for differentiating inflammatory myopa- bodies against endothelial cells) is an early event
thies from toxic or dystrophic myopathies.1-5 leading to the formation of C3b, C3bNEO, and mem-
brane attack complexes (MACs), which are deposited
MRI can be used to identify edema, inflam- on the endothelial cell wall of the endomysial capillar-
mation in muscle or fascia, fatty infiltration, fi- ies; this results in the destruction of capillaries, isch-
brosis, or atrophy. It is useful for assessing the emia, or microinfarcts, which are most prominent in
extent and selectivity of muscle involvement, es- the periphery of the fascicles, as well as in perifascicu-
pecially in cases of inclusion-body myositis; for lar atrophy. Cytokines released by activated comple-
ment lead to the activation of CD4+ T cells, macro-
identifying disease activity; and for guiding the phages, B cells, and CD123+ plasmacytoid dendritic
selection of the muscle with the greatest degree cells; enhance the expression of vascular-cell adhesion
of inflammation to biopsy.3,4,6,7 molecules (VCAMs) and intercellular adhesion molecule
Examination of muscle-biopsy samples reveals (ICAM) on the endothelial cell wall; and facilitate lym-
features distinct to each disease subtype, and phoid cell transmigration to endomysial tissue through
the action of their integrins, late activation antigen
although the results are not always typical or (VLA)–4, and lymphocyte function–associated antigen
specific, it remains the most important diagnos- (LFA)–1, which bind VCAM-1 and ICAM-1. The perifas-
tic tool. Muscle biopsy is most useful when the cicular regions contain fibers that are in a state of re-
biopsy site is properly chosen (i.e., in a muscle modeling and regeneration (expressing TGF-β, NCAM,
that does not have clinical signs of advanced or and Mi-2), cell stress (expressing heat shock protein 70
[HSP70] and HSP90), and immune activation (express-
end-stage disease but is also not minimally af- ing major histocompatibility complex [MHC] class I an-
fected), the specimen is processed at an experi- tigen, chemokines, and STAT1), as well as molecules as-
enced laboratory, and the findings are inter- sociated with innate immunity (such as MxA, ISG15,
preted in the context of the clinical picture.1-3,24,25 and retinoic acid–inducible gene 1 [RIG-1]).
In dermatomyositis, the inflammation is peri-
vascular and is most prominently located in the myositis, when the skin changes are absent or
interfascicular septae or the periphery of the transient)1-5,10,24,25 (Fig. 1A).
fascicles. The muscle fibers undergo necrosis and In polymyositis and inclusion-body myositis,
phagocytosis — often in a portion of a muscle the inflammation is perivascular and is most
fasciculus or the periphery of the fascicle — typically concentrated in multiple foci within the
owing to microinfarcts that lead to hypoperfu- endomysium; it consists predominantly of CD8+
sion and perifascicular atrophy.1-5 Perifascicular T cells invading healthy-appearing, nonnecrotic
atrophy, which is characterized by layers of atro- muscle fibers expressing major histocompatibil-
phic fibers at the periphery of the fascicles, often ity complex (MHC) class I antigen (normal mus-
with perivascular and interfascicular infiltrates, cle fibers do not express this antigen) (Fig. 2A,
is diagnostic of dermatomyositis (or of overlap 2C, and 2D). The finding of MHC expression and

A B
C D
E Possible NO R M A L F A S CICLE D A M A GE D F A S CICLE S

antibodies against
C1 D
endothelial cells Degenerating,
C4 C3 necrotic, and
C2 B Myocyte Capillary Perifascicular Lumen atrophic myocytes
? destruction atrophy enlargement
E ND OT HE LIUM Capillary
C3
C3bNEO
C3a C3b Capillary

MAC MAC damage
Cytokines
MAC ROP HAG E

NO
TNF-α
Mac-1 Molecules Overexpressed
MAC RO P HA GE Cytokines
VLA-4 in the Perifascicular Region
VCAM-1 STAT1 NCAM
T C E LL MHC class I Mi-2
Chemokines MxA, ISG15
B CE LL
HSP70, 90 RIG-1
LFA-1 TGF-β
VESSEL T C E LL ICAM-1
L UMEN Antibody production
CD 1 2 3 +
(Mi-2, MDA-5,
TIF-1, NXP-2)
Chemokines
CD8+ T cells (termed the MHC–CD8 complex) is In necrotizing autoimmune myositis, there are
useful for confirming the diagnosis and for rul- abundant necrotic fibers invaded or surrounded
ing out disorders with nonimmune inflamma- by macrophages (Fig. 2E and 2F). Lymphocytic
tion, as seen in some muscular dystrophies.2,3,5,17,25 infiltrates are sparse, and MHC class I up-regu-

lation is often prominent beyond the necrotic fi-

Figure 2 (facing page). Main Inflammatory Features
bers.3,4,6,14,25 Necrotizing autoimmune myositis is of Polymyositis, Inclusion-Body Myositis, and Necrotiz-
most often mediated by specific antibodies against ing Autoimmune Myositis and a Proposed Immuno-
SRP or HMGCR (see the Glossary), often with pathogenic Scheme for Polymyositis and Inclusion-
complement deposits on capillaries.15,16 Body Myositis.
Inclusion-body myositis has all the inflamma- Panels A and B show cross-sections of hematoxylin
and eosin–stained muscle-biopsy samples from a pa-
tory features of polymyositis, including the CD8–
tient with polymyositis (Panel A) and a patient with in-
MHC complex, but in addition has chronic myo- clusion-body myositis (Panel B), in which scattered in-
pathic changes with increases in connective tissue flammatory foci with lymphocytes invading or
and in the variability in fiber size, autophagic surrounding healthy-appearing muscle fibers are visi-
vacuoles that have walls lined internally with ble. In inclusion-body myositis, there are also chronic
myopathic features (increases in connective tissue and
material that stains bluish-red with hematoxylin
atrophic and hypertrophic fibers) and autophagic vacu-
and eosin or modified Gomori trichrome (Fig. 2B), oles with bluish-red material, most prominent in fibers
“ragged-red” or cytochrome oxidase–negative fi- not invaded by T cells (arrow). In both polymyositis
bers representing abnormal mitochondria, and and inclusion-body myositis, the cells surrounding or
congophilic amyloid deposits next to the vacu- invading healthy fibers are CD8+ T cells, stained in
green with an anti-CD8+ monoclonal antibody (Panel
oles, which are best visualized with crystal violet
C); also visible is widespread expression of MHC class
or fluorescent optics.3-5,20-23 Electron microscopy I, shown in green in Panel D, even in fibers not invad-
shows tubulofilaments 12 to 16 nm in diameter ed by T cells. In contrast, in necrotizing autoimmune
next to the vacuoles.20 In up to 30% of patients myositis (a cross-section stained with trichrome is
with the typical clinical inclusion-body myositis shown in Panel E), there are scattered necrotic fibers
invaded by macrophages (Panel F), which are best vi-
phenotype, vacuoles or amyloid deposits are not
sualized with an acid phosphatase reaction (in red).
found in the muscle-biopsy sample and only in- Panel G shows a proposed mechanism of T-cell–medi-
flammation is seen, which leads to an erroneous ated muscle damage in polymyositis and inclusion-
diagnosis of polymyositis.26 Such patients have body myositis. Antigen-specific CD8+ cells, expanded
“clinical inclusion-body myositis” diagnosed on in the periphery and subsequently in the endomysium,
cross the endothelial cell wall and bind directly to aber-
the basis of clinicopathologic correlation.27,28 Data-
rantly expressed MHC class I on the surface of muscle
driven criteria confirm that finger-flexor or quad- fibers through their T-cell receptors, forming the
riceps weakness, inflammation around nonne- MHC–CD8 complex. Up-regulation of costimulatory
crotic fibers with MHC class I expression, and molecules (BB1 and ICOSL) and their ligands (CD28,
cytochrome oxidase–negative fibers, even without CTLA-4, and ICOS), as well as ICAM-1 or LFA-1, stabi-
lizes the synaptic interaction between CD8+ cells and
vacuoles, are specific for the diagnosis of clini-
MHC class I on muscle fibers. Regulatory Th17 cells
cal inclusion-body myositis.27,28 play a fundamental role in T-cell activation. Perforin
Autoantibodies directed against nuclear RNAs granules released by the autoaggressive T cells medi-
or cytoplasmic antigens are detected in up to 60% ate muscle-fiber necrosis. Cytokines, such as
of patients with inflammatory myopathies,6,7,16,29 interferon-γ, interleukin-1, and tumor necrosis factor
(TNF) released by the activated T cells, may enhance
depending on the case series and the method of
MHC class I up-regulation and T-cell cytotoxicity. Acti-
detection used. Although the pathogenic role of vated B cells or plasmacytoid dendritic cells are clonal-
the antibodies is unclear, some appear to be spe- ly expanded in the endomysium and may participate in
cific for distinct clinical phenotypes and HLA-DR the process in a still-undefined role, either as antigen-
genotypes. These antibodies include those against presenting cells or through the release of cytokines
and antibody production.
aminoacyl tRNA synthetases (ARSs), which are
detected in 20 to 30% of patients.7,16 Among the
eight different ARSs that have been identified, In one rare case, γδ T cells were found to recog-
anti-Jo-1, the most widely commercially available nize ARS, which provided the first pathogenic link
antibody, accounts for 75% of all antisynthetas- between ARS and T-cell–mediated immunity.30
es associated with the antisynthetase syndrome. Necrotizing autoimmune myositis–specific
This syndrome is characterized by myositis with antibodies are directed against the translational
prominent pathologic changes at the periphery transport protein SRP or against HMGCR, the
of the fascicles and the perimysial connective pharmacologic target of statins.15,16 Anti-HMGCR,
tissue,10 interstitial lung disease, arthritis, Rayn- seen in 22% of persons with necrotizing autoim-
aud’s phenomenon, fever, and mechanic’s hands.7 mune myositis, regardless of statin use, correlates

A B C
D E F
G B cells may serve as

antigen-presenting cells
B CE LL
VESSEL B C E LL and secrete antibodies
L UMEN and cytokines
Endothelium
MACR OPHAGE
T H1 7
R E GU LA T O R Y M Y O CYTE
CE LLS CD 8 +
T CE LL
Cytokines and
CD28
MHC chemokines CD40
class I CTLA-4
VCAM-1 ICOS
complex Cytokines CD 8 +
T CEL L ICAM-1 CD80 ICOSL T CE LL
BB1 ICOSL CD40L
MHC
Chemokine class I Perforin
ICAM-1
receptor complex
Necrosis
E ND OT HE LIUM
MHC
class I
complex
VLA-4 VCAM
VCAM-1
T C E LL
ICAM-1
ICAM
LFA-1
with creatine kinase levels and strength.31 Derma- protein 2 (anti-NXP-2), which are usually present
tomyositis-associated antibodies include anti-Mi-2, in patients with cancer-associated adult derma-
which is associated with the typical skin lesions; tomyositis,29 although their presence is influ-
anti-MDA-5, which is associated primarily with enced by geographic, racial, and genetic factors.
amyopathic dermatomyositis or interstitial lung Anti–cytosolic 5′-nucleotidase 1A (anti-cN1A) is
disease4,6,16; and anti–transcriptional intermedi- detected in 60 to 70% of patients with inclusion-
ary factor 1γ (anti-TIF-1γ) and anti–nuclear matrix body myositis,32,33 although the degree of sensi-

tivity and specificity varies according to the meth- surface of the muscle fibers, which cause myo-
od of detection used, and indicates B-cell activation. necrosis on release.42 Analysis of T-cell–receptor
molecules expressed by the infiltrating CD8+
T cells reveals clonal expansion of T-cell–recep-
Pathol o gic Mech a nisms
tor chains and conserved sequences in the anti-
Immunopathology gen-binding region, which suggests an antigen-
The causes of inflammatory myopathies are un- driven T-cell response.43,44 This is further supported
known, but an autoimmune pathogenesis is by the expression of costimulatory molecules and
strongly implicated. In dermatomyositis, comple- up-regulation of adhesion molecules, chemokines,
ment C5b-9 membranolytic attack complex is acti- and cytokines45-47 (Fig. 2G). Th17 and regulatory
vated early (before the destruction of muscle fi- T cells participate in the immune process.48 The
bers is evident) and deposited on the endothelial up-regulation and overload of MHC class I may
cells, leading to necrosis, reduction of the density also cause glycoprotein misfolding, which stress-
of endomysial capillaries, ischemia, and muscle- es the endoplasmic reticulum of the myofibers.49
fiber destruction resembling microinfarcts1-6,24,25,34; B-cell activation also occurs, most prominently
the remaining capillaries have dilated lumens to in inclusion-body myositis50 (although it is un-
compensate for the ischemia2,3,25 (Fig. 1A through clear whether the muscle can sustain germinal
1D). The residual perifascicular atrophy reflects center formations), in which anti-cN1A autoan-
the endofascicular hypoperfusion, which is most tibodies are also detected (see the Glossary).
prominent at the periphery of the fascicles.2,3,24,25 The factors that trigger inflammatory muscle
The activation of membrane attack complex, diseases remain unknown. Genetic risk factors
presumably by antibodies, triggers the release of regulating immune responses against undefined
proinflammatory cytokines, up-regulates adhe- environmental agents have been proposed.7
sion molecules on endothelial cells, and facili- Genetic interactions are supported by the associa-
tates migration of activated lymphocytes, including tions between HLA-DRB1*03 and anti-Jo-1, be-
B cells, CD4+ T cells, and plasmacytoid dendritic tween HLA-DRB1*11:01 and anti-HMGCR–pos-
cells, to the perimysial and endomysial spaces itive necrotizing autoimmune myositis, and
(Fig. 1E). Innate immunity also plays a role that is between HLA-DRB1*03:01 and HLA-DRB1*01:01
based on increased expression of type I interferon– and inclusion-body myositis.51 Viruses may be
inducible proteins in the perifascicular region,35 responsible for disrupting immune tolerance, but
an area where other inflammatory, degenerative, attempts to amplify viruses — including coxsacki-
or regenerative molecules are also overexpressed eviruses, influenza virus, paramyxoviruses (includ-
(Fig. 1E); it remains to be determined whether the ing mumps virus), cytomegalovirus, and Epstein-
effect of innate immunity is caused by retinoic Barr virus — from the muscles have failed.1-5
acid–inducible gene 1 signaling in response to The best evidence for a viral connection involves
local signals from the damaged fibers, which retroviruses, because polymyositis or inclusion-
leads to autoamplification of perifascicular in- body myositis develops in people infected with
flammation by activating interferon-β and MHC human immunodeficiency virus (HIV) or human
class I36 (Fig. 1E). In juvenile dermatomyositis, T-cell lymphotropic virus I.52,53 However, retrovi-
maternal chimeric cells may contribute to the ral antigens are detected only in endomysial
pathogenesis of the disease.37 macrophages and not within the muscle fibers.
In polymyositis and inclusion-body myositis, The autoinvasive T cells are clonally driven, and
CD8+ cytotoxic T cells surround and invade some are retroviral-specific.52 HIV-associated poly-
healthy-appearing, nonnecrotic muscle fibers that myositis and HIV-associated inclusion-body my-
aberrantly express MHC class I (Fig. 2A through ositis should be distinguished from a toxic mi-
2D).38,39 MHC class I expression, which is absent tochondrial myopathy induced by antiretroviral
from the sarcolemma of normal muscle fibers, is drugs, which improves when the drugs are dis-
probably induced by cytokines secreted by acti- continued.54
vated T cells.40,41 The CD8–MHC class I complex
is characteristic of polymyositis and inclusion- Degenerative Component of Inclusion-Body
body myositis, and its detection aids in confirm- Myositis
ing the histologic diagnosis.2-5,25 The CD8+ T cells Inclusion-body myositis is a complex disorder be-
contain perforin granules directed toward the cause, in addition to the autoimmunity compo-

Possible triggers:
Viruses
Muscle aging
Chronic inflammation
Abnormal proteostasis
HLA genotypes
MYOCYTE
Impaired autophagy
Other
MHC
class I CYTOTOX IC Degeneration
CD8+ T CELL
complex
Cytokines
(e.g., interleukin-1β
interleukin-1
Perforin and interferon-γ)
interferon- DA MA G E D
and chemokines F A SC IC LE
Accumulation of
D AMAG ED misfolded proteins,
FASCICLE p-tau, ubiquitin
HE A LT HY
FA S C I C LE
Cell stress and fiber damage Autophagic

vacuole
β-amyloid
-amyloid precursor
Healthy myocytes DA MA
MAGED protein, amyloid-β
amyloid-β42,
amyloid-
Capillary F A SC IC LE and related proteins
Degenerating
CD8+ T Cell Autophagic
myocytes
vacuole
Figure 3. Proposed Mechanisms in Inclusion-Body Myositis.

Shown is a hypothetical schematic diagram of the pathogenesis of inclusion-body myositis, highlighting the interaction between the
long-standing chronic inflammatory process and degeneration, which leads to cell stress and deposits of β-amyloid precursor protein,
amyloid-β42, and misfolded proteins similar to the ones seen in neuroinflammatory disorders such as Alzheimer’s disease. Therefore,
inclusion-body myositis can be considered to be a peripheral model of neuroinflammation. The factors that trigger the disease are un-
clear, but viruses, muscle aging, protein misregulation (such as abnormal proteostasis), impaired autophagy, and HLA genotypes may
play a role, either alone or in combination. Whether the primary event is inflammatory or degenerative is highly debated and remains
unclear.
nent, there is an important degenerative compo- the muscle fibers with the use of immunostain-
nent, highlighted by the presence of congophilic ing, have been advocated as diagnostic markers.20,55
amyloid deposits within some fibers.20-22 Similar In vitro evidence suggests that amyloid-β42 and
to what is seen in Alzheimer’s disease, these its oligomers are involved in the pathway of in-
deposits immunoreact against amyloid precursor tracellular toxicity,20 but it remains unclear how
protein, amyloid-β42, apolipoprotein E, α-synuclein, these proteinaceous aggregates, which are also
presenilin, ubiquitin, and phosphorylated tau, seen in other vacuolar myopathies, induce an in-
which indicates the presence of protein aggrega- flammatory and degenerative myopathy and what
tion.20 Deposits of TDP43, a DNA-binding pro- triggers disease, inflammation, or protein aggre-
tein aberrantly translocated from the nuclei to the gation.21 Laser microdissection of T-cell–invaded
cytoplasm, and p62, a shuttle protein that trans- fibers in comparison with noninvaded or vacuolat-
ports polyubiquitinated proteins, detected within ed fibers has revealed differential up-regulation

Table 2. Treatment of Inflammatory Myopathies: A Step-by-Step Approach.
Treatment for Dermatomyositis, Polymyositis, Treatment for Inclusion-Body

Scenario and Necrotizing Autoimmune Myositis Myositis
Initiation of therapy
New-onset disease Prednisone (1 mg per kilogram, up to 100 mg Physical therapy; participation
per day) for 4–6 weeks; taper to alternate in research trial
days
When weakness at onset is Intravenous glucocorticoids (1000 mg per day) Not applicable
severe or rapidly worsening for 3 to 5 days, then switch to oral regimen
For glucocorticoid sparing, if the Azathioprine, methotrexate, mycophenolate, Not applicable†
patient’s condition cyclosporine*
responds to glucocorticoids
If response to glucocorticoids is Intravenous immune globulin (2 g per kilogram Not applicable‡
insufficient in divided doses over a period of 2 to 5 con-
secutive days)
If response to glucocorticoids and Reevaluate and reconsider diagnosis; initiate Participation in research trial
intravenous immune globu- treatment with rituximab§ if diagnosis is re-
lin is insufficient confirmed, recommend participation in a re-
search trial¶ if disease does not respond to
rituximab
* The use of these agents is based on experience but not on controlled studies. Azathioprine can be given at a dose of up
to 3 mg per kilogram, methotrexate at a dose of up to 20 mg per week, mycophenolate at a dose of 2000 to 3000 mg
per day, and cyclosporine at a dose of up to 300 mg daily. Intravenous cyclophosphamide (0.8 to 1 g per square meter
of body surface area) and oral tacrolimus (4–8 mg per day) may help patients with interstitial lung disease.
† All glucocorticoid-sparing agents are ineffective, either alone or in combination.
‡ In some patients, the dysphagia responds to intravenous immune globulin.
§ Efficacy has not been established with a controlled study, but the evidence of efficacy is compelling.
¶ Candidate agents include eculizumab, alemtuzumab, tocilizumab (anti–interleukin-6), anti–interleukin-17, and anti–
interleukin-1β.
of inflammatory signaling, such as interferon-γ– munosuppressant agent from the outset.6,61 In

receptor signaling.56 Compelling evidence suggests patients with rapidly worsening disease, it is pref-
that aging, abnormal proteostasis (the network erable to administer intravenous methylprednis-
controlling proteins),20 impaired autophagy, cell olone at a dose of 1000 mg per day for 3 to 5 days
stress induced by MHC class I or nitric oxide,21,57 before starting treatment with oral glucocorti-
long-standing inflammation, and proinflam- coids. After 3 to 4 weeks, prednisone is tapered,
matory cytokines such as interferon-γ and as dictated by the response of the disease to
interleukin-1β57,58 may cumulatively trigger or en- therapy, preferably by a switch from a daily dose
hance degeneration, leading to further accumu- to doses on alternate days60; however, if the ob-
lation of stressor molecules and misfolded pro- jective signs of increased strength and ability to
teins59 (Fig. 3). perform activities in daily living are absent at
that time, tapering is accelerated so that treat-
ment with a next agent can be started. A tactical
T r e atmen t of Der m at om yosi t is,
P olym yosi t is, a nd Necro t i zing error is the practice of “chasing” the creatine
Au t oim mune M yosi t is kinase level as a sign of response, especially in
patients who report a sense of feeling better but
Strategies for the treatment of the inflammatory not necessarily of feeling stronger. When the
myopathies are described in Table 2. Oral pred- strength improves, the serum creatine kinase level
nisone administered once daily after breakfast at drops, but a decrease in creatine kinase alone is
a dose of 1 mg per kilogram of body weight, up not a sign of improvement.60
to 100 mg per day, is the first-line drug for the For patients in whom glucocorticoids produce
treatment of dermatomyositis, polymyositis, and a response, azathioprine, mycophenolate mofetil,
necrotizing autoimmune myositis; this choice of methotrexate, or cyclosporine can be used em-
drug is based on experience but not on controlled pirically for glucocorticoid sparing.2-4,6,60,61 When
trials.1-6,60,61 Some clinicians prefer to add an im- interstitial lung disease is a coexisting condition,

cyclophosphamide or tacrolimus may be help- evaluated in an ongoing trial (EudraCT number,

ful.6,60,62 In patients with dermatomyositis, topi- 2012-005772-34). Overall, the long-term outcome
cal glucocorticoids or calcineurin inhibitors and of inflammatory myopathies has substantially
sunlight avoidance are recommended. When glu- improved, with a 10-year survival rate of more
cocorticoids fail to induce remission or in severe than 90%.72
and rapidly progressive cases, intravenous im-
mune globulin therapy (2 g per kilogram in di- T r e atmen t of Inclusion-Body
vided doses over a period of 2 to 5 consecutive M yosi t is
days) is appropriate.2-4,6,60,61 In a double-blind
study, intravenous immune globulin was found to Because of T-cell–mediated cytotoxic effects and
be effective in the treatment of refractory derma- the enhancement of amyloid-related protein ag-
tomyositis63; monthly infusions may be required gregates by proinflammatory cytokines in pa-
to maintain remission.60,63 In open-label trials, tients with inclusion-body myositis,21,57,58 immu-
intravenous immune globulin has also appeared nosuppressive agents have been tried as treatment
to be effective in the treatment of polymyositis for this disease subtype, but all have failed,
and necrotizing autoimmune myositis.6,60 Subcuta- probably because the disease starts long before
neous immune globulin has appeared to sustain patients seek medical advice, when the degen-
remission in small-scale, uncontrolled studies.64 erative cascade is already advanced.60 Glucocorti-
If the disease has not responded to glucocor- coids, methotrexate, cyclosporine, azathioprine,
ticoids and intravenous immune globulin, the and mycophenolate are ineffective, and although
patient should be reevaluated, and if there are some patients may initially have mild subjective
diagnostic uncertainties, a repeat muscle biopsy improvements when treated with one of these
should be considered. If the diagnosis is recon- agents,60,61 no long-term benefit is achieved.73 In-
firmed, biologic agents that have been approved travenous immune globulin has been found to be
for the treatment of other immune diseases may ineffective in controlled trials but may transiently
be considered as experimental treatment options.60 help some patients, especially those with dyspha-
These include rituximab (an anti-CD20 antibody), gia.74,75 Alemtuzumab may provide short-term sta-
which at a dose of 2 g (divided into two infu- bilization,76 but a controlled study is needed.
sions 2 weeks apart) seems effective in some Treatment with anakinra has also not been suc-
patients with dermatomyositis, polymyositis, or cessful.77 Trials targeting muscle-inhibiting TGF-β
necrotizing autoimmune myositis. In a placebo- molecules or muscle growth factors are in prog-
controlled study involving 200 patients, at week ress. Bimagrumab, an antibody that inhibits the
8 there was no difference between the placebo signaling of a TGF-β superfamily receptor, was
group and the rituximab group, and on the basis shown in a small-scale study to increase muscle
of the study design, the results were not signifi- volume after 8 weeks,78 which has prompted an
cant; however, at week 44, when all the patients ongoing controlled study (ClinicalTrials.gov num-
had received rituximab, 83% met the definition ber, NCT01925209). A small, controlled, proof-of-
of improvement.65 Patients with anti-Jo-1, anti- concept study of arimoclomol (ClinicalTrials.gov
Mi-2, or anti-SRP antibodies seem more likely to number, NCT00769860), an agent that up-regu-
have a response.66,67 Tumor necrosis factor inhibi- lates heat shock protein response and attenuates
tors (infliximab, adalimumab, and etanercept) are cell stress, has been completed; the drug had an
ineffective and may worsen or trigger disease.68 acceptable adverse-event profile, but whether there
Other biologics that may be considered as experi- were clinically meaningful benefits is still un-
mental treatment include alemtuzumab, which clear.79
is reportedly effective in polymyositis69; anti-com- At present, symptomatic therapies are the
plement C3 (eculizumab), which is effective in best option. For life-threatening dysphagia that
complement-mediated diseases and may be ef- is not responding to intravenous immune globu-
fective for the treatment of dermatomyositis and lin, cricopharyngeal dilation or myotomy may be
necrotizing autoimmune myositis; anti–interleu- considered. As with all inflammatory myopa-
kin-6 (tocilizumab)70 and anti–interleukin-1 re- thies, nonfatiguing resistance exercises and oc-
ceptor (anakinra),71 which have been effective in cupational and rehabilitation therapies are use-
anecdotal cases; anti–interleukin-17; and anti– ful to improve ambulation, prevent falling, avoid
interleukin-1β (gevokizumab), which is being disuse atrophy, and prevent joint contractures.80

Although the life expectancy of patients with zyme and lecture fees from Baxter and Octapharma. No other
potential conflict of interest relevant to this article was reported.
inclusion-body myositis is normal, most patients
Disclosure forms provided by the author are available with the
with end-stage disease require assistive devices full text of this article at NEJM.org.
such as a cane, walker, or wheelchair.23 I thank all the clinical and research fellows who participated
Dr. Dalakas reports having served on a data and safety moni- in my studies over many years, the numerous clinicians and
toring board for Baxter, serving on steering committees for scientists for their enormous contributions to the field, and all
Grifols/Talecris, Novartis, and Servier, and receiving consulting the patients who participated in my research and continue to
fees from Baxter, Therapath Laboratory, CSL Behring, and Gen- teach me about these diseases.
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Review Article
Dan L. Longo, M.D., Editor

Marinos C. Dalakas, M.D.
I
From the Department of Neurology, nflammatory myopathies are the largest group of potentially
Neuromuscular Division, Thomas Jeffer- treatable myopathies in children and adults. They constitute a heterogeneous
son University, Philadelphia; and Neuro-
immunology Unit, University of Athens group of disorders that are best classified, on the basis of distinct clinicopatho-
Medical School, Athens. Address reprint logic features, in four subtypes: dermatomyositis, polymyositis, necrotizing auto-
requests to Dr. Dalakas at the Depart- immune myositis, and inclusion-body myositis (throughout this review, I use this
ment of Neurology, Neuromuscular Divi-
sion, Thomas Jefferson University, 901 term to refer specifically to sporadic inclusion-body myositis).1-6 A fifth subtype,
Walnut St., Philadelphia, PA 19107, or at termed overlap myositis, is also beginning to be recognized. The identification of
marinos.dalakas@jefferson.edu. the correct subtype and the distinction of these conditions from other diseases
N Engl J Med 2015;372:1734-47. that have characteristics that mimic these conditions is fundamental, because each
DOI: 10.1056/NEJMra1402225 subtype has a different prognosis and response to therapies. This review reflects
Copyright © 2015 Massachusetts Medical Society.
the current knowledge of these conditions, highlights how best to avoid erroneous
diagnoses, describes the main clinicopathologic and immunologic features, and pro-
vides practical guidelines regarding therapies.
Gener a l Cl inic a l Fe at ur e s
Patients with inflammatory myopathies have increasing difficulty with tasks re-
quiring the use of proximal muscles, such as getting up from a chair, climbing steps,
or lifting objects.1-6 Tasks requiring distal muscles, such as buttoning or holding
objects, are affected early in inclusion-body myositis but only in advanced cases of
polymyositis, dermatomyositis, and necrotizing autoimmune myositis. The ocular
muscles are spared in all subtypes, but facial muscles are commonly affected in
inclusion-body myositis.3 In all disease subtypes, neck-extensor and pharyngeal
muscles can be involved, which results in difficulty holding up the head (head drop)
or in dysphagia. In advanced and rare acute cases, the respiratory muscles can be
affected. Muscle atrophy is detected early in inclusion-body myositis, with selective
atrophy of the quadriceps and forearm muscles, but it develops in all subtypes if
the weakness is severe and chronic. Myalgia and muscle tenderness may occur,
especially in patients with the antisynthetase syndrome (see the Glossary),6,7 but if
pain is severe and the weakness follows a “breakaway” pattern, in which the pa-
tient has difficulty sustaining effort, fasciitis or fibromyalgia should be ruled out.
Extramuscular manifestations may occur in all inflammatory myopathies, al-
though they occur in inclusion-body myositis only in rare cases; these manifesta-
tions include systemic symptoms, such as fever, arthralgia, and Raynaud’s phe-
nomenon, as seen in the antisynthetase syndrome4,6,7; cardiac arrhythmias or
ventricular dysfunction, in relatively uncommon cases in which the affected car-
diac muscle is clinically symptomatic; and pulmonary complications, due primar-
ily to interstitial lung disease, which are reported in 10 to 40% of patients.8 The
prevalence of interstitial lung disease, a condition that is best detected with high-
resolution computed tomography, is as high as 70% among patients with anti–his-
tidyl–transfer RNA (tRNA) synthetase (anti-Jo-1) or anti–melanoma differentiation–

Glossary
Anti–cytosolic 5′-nucleotidase 1A (anti-cN1A, or anti-NT5C1A): Autoantibody directed against the cN1A nuclear protein
involved in RNA processing; associated with inclusion-body myositis.
Anti–histidyl–transfer RNA synthetase (anti-Jo-1): The most common autoantibody associated with the antisynthetase
syndrome, which consists of myopathy, fever, interstitial lung disease, Raynaud’s phenomenon, arthritis, and “me-
chanic’s hands.”
Anti–3-hydroxy-3-methylglutaryl–coenzyme A reductase (anti-HMGCR): Autoantibody directed against HMGCR, the
pharmacologic target of statins; specific for necrotizing autoimmune myositis.
Anti–melanoma differentiation–associated protein-5 (anti-MDA-5): Autoantibody directed against a cytoplasmic RNA-
specific helicase; associated with amyopathic dermatomyositis or rapidly progressive interstitial lung disease.
Anti-Mi-2: Autoantibody directed against a nuclear DNA helicase involved in transcriptional activation; associated with
typical skin lesions of dermatomyositis.
Anti–signal recognition particle (anti-SRP): Autoantibody directed against a polypeptide complex involved in protein
transport to endoplasmic reticulum; specific for necrotizing autoimmune myositis.
Anti–transcriptional intermediary factor 1 γ (anti-TIF-1γ): Autoantibody involved in cell growth and differentiation; seen
in cancer-associated dermatomyositis, along with anti–nuclear matrix protein 2 (anti-NXP-2).
associated protein (MDA)–5 antibodies (see the bined with a red flush on the face, fatigue, and
Glossary).6-8 a reluctance to socialize.2,3
The symptoms of dermatomyositis may over-
lap with those of systemic sclerosis and mixed
Specific Cl inic a l Fe at ur e s
connective-tissue disease1-7; in such cases, the typi-
Dermatomyositis cal skin rash is transient or faint. Overlap myo-
The specific clinical features of inflammatory sitis is now starting to be recognized as a dis-
myopathies are described in Table 1 and in the tinct entity; it manifests without the rash that is
Supplementary Appendix, available with the full typical of dermatomyositis, with prominent patho-
text of this article at NEJM.org. Dermatomyositis logic changes in the perifascicular, interfascicular,
is seen in both children and adults, and the early and perimysial regions, and is frequently associ-
symptoms include distinct skin manifestations ated with antisynthetase antibodies.10 In adults,
accompanying or preceding muscle weakness; the the risk of cancer is increased during the first
skin manifestations include periorbital heliotrope 3 to 5 years after the onset of dermatomyositis,
(blue–purple) rash with edema; erythematous rash with reported a frequency of 9 to 32%.11,12 The
on the face, knees, elbows, malleoli, neck, anterior most common cancers are ovarian cancer, breast
chest (in a V-sign), and back and shoulders (in a cancer, colon cancer, melanoma, nasopharyngeal
shawl sign); and a violaceous eruption (Gottron’s cancer (in Asians), and non-Hodgkin’s lymphoma;
rash) on the knuckles, which may evolve into a the risk of these cancers necessitates a thorough
scaling discoloration.1-7,9 The lesions are photo- annual workup in the first 3 years after disease
sensitive and may be aggravated by ultraviolet onset.11,12
radiation.6,7,9 Dilated capillary loops at the base
of the fingernails, irregular and thickened cuti- Polymyositis
cles, and cracked palmar fingertips (“mechanic’s Polymyositis is rare as a stand-alone entity and
hands”) are characteristic of dermatomyositis.1-3 is often misdiagnosed; most patients whose con-
Subcutaneous calcifications, sometimes extrud- dition has been diagnosed as polymyositis have
ing to the surface of the skin and causing ulcer- inclusion-body myositis, necrotizing autoimmune
ations and infections, may occur and are espe- myositis, or inflammatory dystrophy.3,13 Polymyo-
cially common among children. If the patient’s sitis remains a diagnosis of exclusion and is best
strength appears to be normal, the dermatomyo- defined as a subacute proximal myopathy in adults
sitis may be limited to the skin (amyopathic der- who do not have rash, a family history of neuro-
matomyositis),9 although subclinical muscle in- muscular disease, exposure to myotoxic drugs
volvement is frequent.1-3 In children, an early (e.g., statins, penicillamine, and zidovudine), in-
symptom is “misery,” defined as irritability com- volvement of facial and extraocular muscles, en-

1736
Table 1. Criteria Supporting the Diagnosis of Inflammatory Myopathies.
Criterion Dermatomyositis Polymyositis Necrotizing Autoimmune Myositis Inclusion-Body Myositis

Pattern of muscle Subacute onset of proximal symmetric Subacute onset of proximal symmetric Acute or subacute onset of proxi- Slow onset of proximal and distal weak-
weakness weakness with characteristic skin weakness in adults (diagnosis is mal, often severe weakness in ness; atrophy of quadriceps and
rash in patients of any age made when other causes have been adults forearms; frequent falls; mild facial
ruled out)* muscle weakness in people older
than 50 years of age
Creatine kinase level High, up to 50 times the upper limit of High, up to 50 times the upper limit of Very high; more than 50 times the Up to 10 times the upper limit of nor-
normal; can at times be normal normal in early active disease; may upper limit of normal in early mal; can be normal or slightly
linger at up to 10 times the upper active disease elevated
The
limit of normal
Electromyography Myopathic units (active and chronic) Myopathic units (active and chronic) Active myopathic units Myopathic units (active and chronic)
with some mixed large-size poten-
tials
Muscle biopsy Perivascular, perimysial, and perifascic- CD8+ cells invading healthy fibers; wide- Scattered necrotic fibers with mac- CD8+ cells invading healthy fibers;
ular inflammation; necrotic fibers in spread expression of MHC class I rophages; no CD8+ cells or vac- widespread expression of MHC
“wedge-like” infarcts; perifascicular antigen; no vacuoles; ruling out of uoles; deposits of complement class I antigen; autophagic vacu-
atrophy; reduced capillaries† inflammatory dystrophies on capillaries‡ oles,§ ragged-red or ragged-blue
fibers; congophilic amyloid depos-
its¶
Autoantibodies Anti-MDA-5, anti-Mi-2; anti-TIF-1 and Antisynthetase antibodies (often seen in Anti-SRP and anti-HMGCR, specif- Anti-cN1A (of uncertain pathologic sig-
anti-NXP-2 (implicated in cancer- overlap myositis) associated with inic for necrotizing autoimmune nificance)
n e w e ng l a n d j o u r na l

associated dermatomyositis) terstitial lung disease, arthritis, myositis
of
fever, and “mechanic’s hands”

Magnetic resonance May show active inflammation May show active inflammation; could May show active inflammation; Shows selective muscle involvement,
imaging guide biopsy site could guide biopsy site but might be difficult to distinguish
n engl j med 372;18 nejm.org April 30, 2015

atrophy from chronic inflammation

m e dic i n e
* Drug-induced myopathies (e.g., penicillamine, statins, or antiretrovirals), inflammatory dystrophies (such as those due to mutations in the genes encoding dysferlin, calpain, or anocta-
min; Becker’s muscular dystrophy; facioscapulohumeral muscular dystrophy; or myofibrillar myopathies), inclusion-body myositis, necrotizing autoimmune myositis, metabolic myopa-
thies, and fasciitis or fibromyalgia need to be ruled out.
† Similar pathologic changes in the perifascicular, perimysial, and interfascicular areas (to a lesser degree of severity) can be seen in overlap myositis (without skin lesions) or the antisyn-
thetase syndrome.
‡ Metabolic muscle diseases presenting as myoglobinuria and toxic or drug-induced myopathies need to be ruled out.
§ In clinical inclusion-body myositis, when patients have the typical inclusion-body myositis phenotype, vacuoles are absent; such patients are erroneously thought to have polymyositis
because of polymyositis-like inflammation; ragged-red fibers or cytochrome oxidase–negative fibers are frequently present and are helpful in diagnosis.
¶ TDP43 and p62 deposits, detected with the use of immunostaining, have been proposed as tissue biomarkers.
docrinopathy, or the clinical phenotype of inclu- quadriceps muscles; frequent falls due to quad-
sion-body myositis.1-3 riceps muscle weakness causing buckling of the
knees; and mild facial-muscle weakness.1-5,20-23 The
Necrotizing Autoimmune Myositis axial muscles may be affected, which results in
Necrotizing autoimmune myositis is a distinct camptocormia (bending forward of the spine) or
clinicopathologic entity that occurs more frequent- head drop. Dysphagia occurs in more than 50%
ly than polymyositis, accounting for up to 19% of the patients.23
of all inflammatory myopathies.13 It can occur at
any age but is seen primarily in adults; it starts Di agnosis
either acutely, reaching its peak over a period of
days or weeks, or subacutely, progressing steadi- The diagnosis of the exact subtype of inflamma-
ly and causing severe weakness and very high tory myopathy is based on the combination of
creatine kinase levels.14,15 Necrotizing autoimmune clinical history, tempo of disease progression,
myositis occurs alone or after viral infections, in pattern of muscle involvement, muscle enzyme
association with cancer, in patients with connec- levels, electromyographic findings, muscle-biopsy
tive-tissue disorders such as scleroderma, or in analysis, and for some conditions, the presence
patients taking statins, in whom the myopathy of certain autoantibodies (Table 1). Typical skin
continues to worsen after statin withdrawal (if changes, with or without muscle weakness, indi-
the myopathy improves within 4 to 6 weeks after cate dermatomyositis; a subacute onset of proxi-
discontinuation of statins, it was probably caused mal myopathic weakness points to polymyositis
by toxic effects of the drug rather than by im- or necrotizing autoimmune myositis; and slowly
mune myopathy).3,4,6,14-16 Most patients with nec- progressive proximal and distal weakness with
rotizing autoimmune myositis have antibodies selective atrophy points to inclusion-body myosi-
against signal recognition particle (SRP) or against tis. Electromyography is diagnostically useful in
3-hydroxy-3-methylglutaryl–coenzyme A reductase all disease subtypes to rule out neurogenic con-
(HMGCR) (see the Glossary).14-16 ditions and assess disease activity. Serum creatine
kinase is elevated in all subtypes, but very high
Inclusion-Body Myositis levels from the outset point to necrotizing auto-
Inclusion-body myositis is the most common and immune myositis. Magnetic resonance imaging
disabling inflammatory myopathy among persons (MRI) is helpful for diagnosis when muscle edema
50 years of age or older.1-5,17-23 Its prevalence, is present or myofasciitis is suspected, as well as
which was initially estimated in the Netherlands for identification of the particular muscles affected
as 4.9 cases per million population,18 is much by atrophy in inclusion-body myositis. Muscle
higher when adjusted for age; in two later stud- biopsy is essential for the diagnosis of polymyo-
ies in Australia and the United States, the age- sitis, overlap myositis, necrotizing autoimmune
adjusted prevalence ranged from 51.3 to 70 cases myositis, and inclusion-body myositis, as well as
per million.19,22 In a small chart-review study con- for ruling out disease mimics such as dystrophies
ducted in one U.S. county, the estimated inci- or metabolic or vacuolar myopathies. Assessment
dence of inclusion-body myositis was 7.9 cases of autoantibodies is helpful for the diagnosis of
per million in the 1980s and 1990s.19 The dis- necrotizing autoimmune myositis and for the
ease starts insidiously and develops over a peri- classification of distinct subtypes and their as-
od of years, at times asymmetrically (i.e., it may sociations with systemic organ involvement, such
start or be more severe in one extremity or on one as interstitial lung disease.
side of the body), and progresses steadily, simu- Among muscle-derived enzymes in serum, the
lating a late-life muscular dystrophy or slowly most sensitive indicator of inflammatory myop-
progressive motor-neuron disease.1-5 Although in- athy is creatine kinase, which is elevated in pa-
clusion-body myositis is commonly suspected tients with active disease. The highest levels, up to
when a patient’s presumed polymyositis does not more than 50 times the upper limit of normal,
respond to therapy,3 features that can lead to an are seen in patients with necrotizing autoimmune
early clinical diagnosis include the early involve- myositis, and the lowest (less than 10 times the
ment of distal muscles, especially foot extensors upper limit of normal) are seen in patients with
and finger flexors; atrophy of the forearms and inclusion-body myositis. Although serum levels

of creatine kinase usually parallel disease activ- Figure 1 (facing page). Dermatomyositis: A Comple-
ity, they can be normal or only slightly elevated ment-Mediated Microangiopathy.
in patients with active dermatomyositis, overlap Panel A shows a cross-section of a hematoxylin and
myositis, or active inclusion-body myositis. Along eosin–stained muscle-biopsy sample with classic der-
with creatine kinase, aspartate aminotransferase matomyositis perifascicular atrophy (layers of atrophic
and alanine aminotransferase levels are also el- fibers at the periphery of the fascicle [arrows]) and
some inflammatory infiltrates. Panel B shows the de-
evated, a sign that is sometimes erroneously in- position of complement (membranolytic attack com-
terpreted as indicating liver disease and that leads plex, in green) on the endothelial cell wall of endo-
to an investigation with a liver biopsy instead of mysial vessels (stained in red with Ulex europaeus
a muscle biopsy. Serum aldolase levels may be lectin), which leads to destruction of endothelial cells
also elevated, especially if the fascia is involved. (shown in orange, indicating the superimposition of
red and green). Consequently, in the muscles of pa-
Electromyography can show myopathic motor- tients with dermatomyositis (shown in Panel C), as
unit potentials (short-duration, low-amplitude compared with a myopathic control (Panel D), the den-
polyphasic units on voluntary activation) and in- sity of the endomysial capillaries (in yellow–red) is re-
creased spontaneous activity with fibrillations, duced, especially at the periphery of the fascicle, with
complex repetitive discharges, and positive sharp the lumen of the remaining capillaries dilated in an ef-
fort to compensate for the ischemic process.1,2 Panel E
waves. These findings are useful in determining shows a schematic diagram of a proposed immuno-
whether the myopathy is active or chronic and in pathogenesis of dermatomyositis. Activation of com-
ruling out neurogenic disorders, but they cannot plement component 3 (C3) (probably triggered by anti-
be used for differentiating inflammatory myopa- bodies against endothelial cells) is an early event
thies from toxic or dystrophic myopathies.1-5 leading to the formation of C3b, C3bNEO, and mem-
brane attack complexes (MACs), which are deposited
MRI can be used to identify edema, inflam- on the endothelial cell wall of the endomysial capillar-
mation in muscle or fascia, fatty infiltration, fi- ies; this results in the destruction of capillaries, isch-
brosis, or atrophy. It is useful for assessing the emia, or microinfarcts, which are most prominent in
extent and selectivity of muscle involvement, es- the periphery of the fascicles, as well as in perifascicu-
pecially in cases of inclusion-body myositis; for lar atrophy. Cytokines released by activated comple-
ment lead to the activation of CD4+ T cells, macro-
identifying disease activity; and for guiding the phages, B cells, and CD123+ plasmacytoid dendritic
selection of the muscle with the greatest degree cells; enhance the expression of vascular-cell adhesion
of inflammation to biopsy.3,4,6,7 molecules (VCAMs) and intercellular adhesion molecule
Examination of muscle-biopsy samples reveals (ICAM) on the endothelial cell wall; and facilitate lym-
features distinct to each disease subtype, and phoid cell transmigration to endomysial tissue through
the action of their integrins, late activation antigen
although the results are not always typical or (VLA)–4, and lymphocyte function–associated antigen
specific, it remains the most important diagnos- (LFA)–1, which bind VCAM-1 and ICAM-1. The perifas-
tic tool. Muscle biopsy is most useful when the cicular regions contain fibers that are in a state of re-
biopsy site is properly chosen (i.e., in a muscle modeling and regeneration (expressing TGF-β, NCAM,
that does not have clinical signs of advanced or and Mi-2), cell stress (expressing heat shock protein 70
[HSP70] and HSP90), and immune activation (express-
end-stage disease but is also not minimally af- ing major histocompatibility complex [MHC] class I an-
fected), the specimen is processed at an experi- tigen, chemokines, and STAT1), as well as molecules as-
enced laboratory, and the findings are inter- sociated with innate immunity (such as MxA, ISG15,
preted in the context of the clinical picture.1-3,24,25 and retinoic acid–inducible gene 1 [RIG-1]).
In dermatomyositis, the inflammation is peri-
vascular and is most prominently located in the myositis, when the skin changes are absent or
interfascicular septae or the periphery of the transient)1-5,10,24,25 (Fig. 1A).
fascicles. The muscle fibers undergo necrosis and In polymyositis and inclusion-body myositis,
phagocytosis — often in a portion of a muscle the inflammation is perivascular and is most
fasciculus or the periphery of the fascicle — typically concentrated in multiple foci within the
owing to microinfarcts that lead to hypoperfu- endomysium; it consists predominantly of CD8+
sion and perifascicular atrophy.1-5 Perifascicular T cells invading healthy-appearing, nonnecrotic
atrophy, which is characterized by layers of atro- muscle fibers expressing major histocompatibil-
phic fibers at the periphery of the fascicles, often ity complex (MHC) class I antigen (normal mus-
with perivascular and interfascicular infiltrates, cle fibers do not express this antigen) (Fig. 2A,
is diagnostic of dermatomyositis (or of overlap 2C, and 2D). The finding of MHC expression and

A B
C D
E Possible NO R M A L F A S CICLE D A M A GE D F A S CICLE S

antibodies against
C1 D
endothelial cells Degenerating,
C4 C3 necrotic, and
C2 B Myocyte Capillary Perifascicular Lumen atrophic myocytes
? destruction atrophy enlargement
E ND OT HE LIUM Capillary
C3
C3bNEO
C3a C3b Capillary

MAC MAC damage
Cytokines
MAC ROP HAG E

NO
TNF-α
Mac-1 Molecules Overexpressed
MAC RO P HA GE Cytokines
VLA-4 in the Perifascicular Region
VCAM-1 STAT1 NCAM
T C E LL MHC class I Mi-2
Chemokines MxA, ISG15
B CE LL
HSP70, 90 RIG-1
LFA-1 TGF-β
VESSEL T C E LL ICAM-1
L UMEN Antibody production
CD 1 2 3 +
(Mi-2, MDA-5,
TIF-1, NXP-2)
Chemokines
CD8+ T cells (termed the MHC–CD8 complex) is In necrotizing autoimmune myositis, there are
useful for confirming the diagnosis and for rul- abundant necrotic fibers invaded or surrounded
ing out disorders with nonimmune inflamma- by macrophages (Fig. 2E and 2F). Lymphocytic
tion, as seen in some muscular dystrophies.2,3,5,17,25 infiltrates are sparse, and MHC class I up-regu-

lation is often prominent beyond the necrotic fi-

Figure 2 (facing page). Main Inflammatory Features
bers.3,4,6,14,25 Necrotizing autoimmune myositis is of Polymyositis, Inclusion-Body Myositis, and Necrotiz-
most often mediated by specific antibodies against ing Autoimmune Myositis and a Proposed Immuno-
SRP or HMGCR (see the Glossary), often with pathogenic Scheme for Polymyositis and Inclusion-
complement deposits on capillaries.15,16 Body Myositis.
Inclusion-body myositis has all the inflamma- Panels A and B show cross-sections of hematoxylin
and eosin–stained muscle-biopsy samples from a pa-
tory features of polymyositis, including the CD8–
tient with polymyositis (Panel A) and a patient with in-
MHC complex, but in addition has chronic myo- clusion-body myositis (Panel B), in which scattered in-
pathic changes with increases in connective tissue flammatory foci with lymphocytes invading or
and in the variability in fiber size, autophagic surrounding healthy-appearing muscle fibers are visi-
vacuoles that have walls lined internally with ble. In inclusion-body myositis, there are also chronic
myopathic features (increases in connective tissue and
material that stains bluish-red with hematoxylin
atrophic and hypertrophic fibers) and autophagic vacu-
and eosin or modified Gomori trichrome (Fig. 2B), oles with bluish-red material, most prominent in fibers
“ragged-red” or cytochrome oxidase–negative fi- not invaded by T cells (arrow). In both polymyositis
bers representing abnormal mitochondria, and and inclusion-body myositis, the cells surrounding or
congophilic amyloid deposits next to the vacu- invading healthy fibers are CD8+ T cells, stained in
green with an anti-CD8+ monoclonal antibody (Panel
oles, which are best visualized with crystal violet
C); also visible is widespread expression of MHC class
or fluorescent optics.3-5,20-23 Electron microscopy I, shown in green in Panel D, even in fibers not invad-
shows tubulofilaments 12 to 16 nm in diameter ed by T cells. In contrast, in necrotizing autoimmune
next to the vacuoles.20 In up to 30% of patients myositis (a cross-section stained with trichrome is
with the typical clinical inclusion-body myositis shown in Panel E), there are scattered necrotic fibers
invaded by macrophages (Panel F), which are best vi-
phenotype, vacuoles or amyloid deposits are not
sualized with an acid phosphatase reaction (in red).
found in the muscle-biopsy sample and only in- Panel G shows a proposed mechanism of T-cell–medi-
flammation is seen, which leads to an erroneous ated muscle damage in polymyositis and inclusion-
diagnosis of polymyositis.26 Such patients have body myositis. Antigen-specific CD8+ cells, expanded
“clinical inclusion-body myositis” diagnosed on in the periphery and subsequently in the endomysium,
cross the endothelial cell wall and bind directly to aber-
the basis of clinicopathologic correlation.27,28 Data-
rantly expressed MHC class I on the surface of muscle
driven criteria confirm that finger-flexor or quad- fibers through their T-cell receptors, forming the
riceps weakness, inflammation around nonne- MHC–CD8 complex. Up-regulation of costimulatory
crotic fibers with MHC class I expression, and molecules (BB1 and ICOSL) and their ligands (CD28,
cytochrome oxidase–negative fibers, even without CTLA-4, and ICOS), as well as ICAM-1 or LFA-1, stabi-
lizes the synaptic interaction between CD8+ cells and
vacuoles, are specific for the diagnosis of clini-
MHC class I on muscle fibers. Regulatory Th17 cells
cal inclusion-body myositis.27,28 play a fundamental role in T-cell activation. Perforin
Autoantibodies directed against nuclear RNAs granules released by the autoaggressive T cells medi-
or cytoplasmic antigens are detected in up to 60% ate muscle-fiber necrosis. Cytokines, such as
of patients with inflammatory myopathies,6,7,16,29 interferon-γ, interleukin-1, and tumor necrosis factor
(TNF) released by the activated T cells, may enhance
depending on the case series and the method of
MHC class I up-regulation and T-cell cytotoxicity. Acti-
detection used. Although the pathogenic role of vated B cells or plasmacytoid dendritic cells are clonal-
the antibodies is unclear, some appear to be spe- ly expanded in the endomysium and may participate in
cific for distinct clinical phenotypes and HLA-DR the process in a still-undefined role, either as antigen-
genotypes. These antibodies include those against presenting cells or through the release of cytokines
and antibody production.
aminoacyl tRNA synthetases (ARSs), which are
detected in 20 to 30% of patients.7,16 Among the
eight different ARSs that have been identified, In one rare case, γδ T cells were found to recog-
anti-Jo-1, the most widely commercially available nize ARS, which provided the first pathogenic link
antibody, accounts for 75% of all antisynthetas- between ARS and T-cell–mediated immunity.30
es associated with the antisynthetase syndrome. Necrotizing autoimmune myositis–specific
This syndrome is characterized by myositis with antibodies are directed against the translational
prominent pathologic changes at the periphery transport protein SRP or against HMGCR, the
of the fascicles and the perimysial connective pharmacologic target of statins.15,16 Anti-HMGCR,
tissue,10 interstitial lung disease, arthritis, Rayn- seen in 22% of persons with necrotizing autoim-
aud’s phenomenon, fever, and mechanic’s hands.7 mune myositis, regardless of statin use, correlates

A B C
D E F
G B cells may serve as

antigen-presenting cells
B CE LL
VESSEL B C E LL and secrete antibodies
L UMEN and cytokines
Endothelium
MACR OPHAGE
T H1 7
R E GU LA T O R Y M Y O CYTE
CE LLS CD 8 +
T CE LL
Cytokines and
CD28
MHC chemokines CD40
class I CTLA-4
VCAM-1 ICOS
complex Cytokines CD 8 +
T CEL L ICAM-1 CD80 ICOSL T CE LL
BB1 ICOSL CD40L
MHC
Chemokine class I Perforin
ICAM-1
receptor complex
Necrosis
E ND OT HE LIUM
MHC
class I
complex
VLA-4 VCAM
VCAM-1
T C E LL
ICAM-1
ICAM
LFA-1
with creatine kinase levels and strength.31 Derma- protein 2 (anti-NXP-2), which are usually present
tomyositis-associated antibodies include anti-Mi-2, in patients with cancer-associated adult derma-
which is associated with the typical skin lesions; tomyositis,29 although their presence is influ-
anti-MDA-5, which is associated primarily with enced by geographic, racial, and genetic factors.
amyopathic dermatomyositis or interstitial lung Anti–cytosolic 5′-nucleotidase 1A (anti-cN1A) is
disease4,6,16; and anti–transcriptional intermedi- detected in 60 to 70% of patients with inclusion-
ary factor 1γ (anti-TIF-1γ) and anti–nuclear matrix body myositis,32,33 although the degree of sensi-

tivity and specificity varies according to the meth- surface of the muscle fibers, which cause myo-
od of detection used, and indicates B-cell activation. necrosis on release.42 Analysis of T-cell–receptor
molecules expressed by the infiltrating CD8+
T cells reveals clonal expansion of T-cell–recep-
Pathol o gic Mech a nisms
tor chains and conserved sequences in the anti-
Immunopathology gen-binding region, which suggests an antigen-
The causes of inflammatory myopathies are un- driven T-cell response.43,44 This is further supported
known, but an autoimmune pathogenesis is by the expression of costimulatory molecules and
strongly implicated. In dermatomyositis, comple- up-regulation of adhesion molecules, chemokines,
ment C5b-9 membranolytic attack complex is acti- and cytokines45-47 (Fig. 2G). Th17 and regulatory
vated early (before the destruction of muscle fi- T cells participate in the immune process.48 The
bers is evident) and deposited on the endothelial up-regulation and overload of MHC class I may
cells, leading to necrosis, reduction of the density also cause glycoprotein misfolding, which stress-
of endomysial capillaries, ischemia, and muscle- es the endoplasmic reticulum of the myofibers.49
fiber destruction resembling microinfarcts1-6,24,25,34; B-cell activation also occurs, most prominently
the remaining capillaries have dilated lumens to in inclusion-body myositis50 (although it is un-
compensate for the ischemia2,3,25 (Fig. 1A through clear whether the muscle can sustain germinal
1D). The residual perifascicular atrophy reflects center formations), in which anti-cN1A autoan-
the endofascicular hypoperfusion, which is most tibodies are also detected (see the Glossary).
prominent at the periphery of the fascicles.2,3,24,25 The factors that trigger inflammatory muscle
The activation of membrane attack complex, diseases remain unknown. Genetic risk factors
presumably by antibodies, triggers the release of regulating immune responses against undefined
proinflammatory cytokines, up-regulates adhe- environmental agents have been proposed.7
sion molecules on endothelial cells, and facili- Genetic interactions are supported by the associa-
tates migration of activated lymphocytes, including tions between HLA-DRB1*03 and anti-Jo-1, be-
B cells, CD4+ T cells, and plasmacytoid dendritic tween HLA-DRB1*11:01 and anti-HMGCR–pos-
cells, to the perimysial and endomysial spaces itive necrotizing autoimmune myositis, and
(Fig. 1E). Innate immunity also plays a role that is between HLA-DRB1*03:01 and HLA-DRB1*01:01
based on increased expression of type I interferon– and inclusion-body myositis.51 Viruses may be
inducible proteins in the perifascicular region,35 responsible for disrupting immune tolerance, but
an area where other inflammatory, degenerative, attempts to amplify viruses — including coxsacki-
or regenerative molecules are also overexpressed eviruses, influenza virus, paramyxoviruses (includ-
(Fig. 1E); it remains to be determined whether the ing mumps virus), cytomegalovirus, and Epstein-
effect of innate immunity is caused by retinoic Barr virus — from the muscles have failed.1-5
acid–inducible gene 1 signaling in response to The best evidence for a viral connection involves
local signals from the damaged fibers, which retroviruses, because polymyositis or inclusion-
leads to autoamplification of perifascicular in- body myositis develops in people infected with
flammation by activating interferon-β and MHC human immunodeficiency virus (HIV) or human
class I36 (Fig. 1E). In juvenile dermatomyositis, T-cell lymphotropic virus I.52,53 However, retrovi-
maternal chimeric cells may contribute to the ral antigens are detected only in endomysial
pathogenesis of the disease.37 macrophages and not within the muscle fibers.
In polymyositis and inclusion-body myositis, The autoinvasive T cells are clonally driven, and
CD8+ cytotoxic T cells surround and invade some are retroviral-specific.52 HIV-associated poly-
healthy-appearing, nonnecrotic muscle fibers that myositis and HIV-associated inclusion-body my-
aberrantly express MHC class I (Fig. 2A through ositis should be distinguished from a toxic mi-
2D).38,39 MHC class I expression, which is absent tochondrial myopathy induced by antiretroviral
from the sarcolemma of normal muscle fibers, is drugs, which improves when the drugs are dis-
probably induced by cytokines secreted by acti- continued.54
vated T cells.40,41 The CD8–MHC class I complex
is characteristic of polymyositis and inclusion- Degenerative Component of Inclusion-Body
body myositis, and its detection aids in confirm- Myositis
ing the histologic diagnosis.2-5,25 The CD8+ T cells Inclusion-body myositis is a complex disorder be-
contain perforin granules directed toward the cause, in addition to the autoimmunity compo-

Possible triggers:
Viruses
Muscle aging
Chronic inflammation
Abnormal proteostasis
HLA genotypes
MYOCYTE
Impaired autophagy
Other
MHC
class I CYTOTOX IC Degeneration
CD8+ T CELL
complex
Cytokines
(e.g., interleukin-1β
interleukin-1
Perforin and interferon-γ)
interferon- DA MA G E D
and chemokines F A SC IC LE
Accumulation of
D AMAG ED misfolded proteins,
FASCICLE p-tau, ubiquitin
HE A LT HY
FA S C I C LE
Cell stress and fiber damage Autophagic

vacuole
β-amyloid
-amyloid precursor
Healthy myocytes DA MA
MAGED protein, amyloid-β
amyloid-β42,
amyloid-
Capillary F A SC IC LE and related proteins
Degenerating
CD8+ T Cell Autophagic
myocytes
vacuole
Figure 3. Proposed Mechanisms in Inclusion-Body Myositis.

Shown is a hypothetical schematic diagram of the pathogenesis of inclusion-body myositis, highlighting the interaction between the
long-standing chronic inflammatory process and degeneration, which leads to cell stress and deposits of β-amyloid precursor protein,
amyloid-β42, and misfolded proteins similar to the ones seen in neuroinflammatory disorders such as Alzheimer’s disease. Therefore,
inclusion-body myositis can be considered to be a peripheral model of neuroinflammation. The factors that trigger the disease are un-
clear, but viruses, muscle aging, protein misregulation (such as abnormal proteostasis), impaired autophagy, and HLA genotypes may
play a role, either alone or in combination. Whether the primary event is inflammatory or degenerative is highly debated and remains
unclear.
nent, there is an important degenerative compo- the muscle fibers with the use of immunostain-
nent, highlighted by the presence of congophilic ing, have been advocated as diagnostic markers.20,55
amyloid deposits within some fibers.20-22 Similar In vitro evidence suggests that amyloid-β42 and
to what is seen in Alzheimer’s disease, these its oligomers are involved in the pathway of in-
deposits immunoreact against amyloid precursor tracellular toxicity,20 but it remains unclear how
protein, amyloid-β42, apolipoprotein E, α-synuclein, these proteinaceous aggregates, which are also
presenilin, ubiquitin, and phosphorylated tau, seen in other vacuolar myopathies, induce an in-
which indicates the presence of protein aggrega- flammatory and degenerative myopathy and what
tion.20 Deposits of TDP43, a DNA-binding pro- triggers disease, inflammation, or protein aggre-
tein aberrantly translocated from the nuclei to the gation.21 Laser microdissection of T-cell–invaded
cytoplasm, and p62, a shuttle protein that trans- fibers in comparison with noninvaded or vacuolat-
ports polyubiquitinated proteins, detected within ed fibers has revealed differential up-regulation

Table 2. Treatment of Inflammatory Myopathies: A Step-by-Step Approach.
Treatment for Dermatomyositis, Polymyositis, Treatment for Inclusion-Body

Scenario and Necrotizing Autoimmune Myositis Myositis
Initiation of therapy
New-onset disease Prednisone (1 mg per kilogram, up to 100 mg Physical therapy; participation
per day) for 4–6 weeks; taper to alternate in research trial
days
When weakness at onset is Intravenous glucocorticoids (1000 mg per day) Not applicable
severe or rapidly worsening for 3 to 5 days, then switch to oral regimen
For glucocorticoid sparing, if the Azathioprine, methotrexate, mycophenolate, Not applicable†
patient’s condition cyclosporine*
responds to glucocorticoids
If response to glucocorticoids is Intravenous immune globulin (2 g per kilogram Not applicable‡
insufficient in divided doses over a period of 2 to 5 con-
secutive days)
If response to glucocorticoids and Reevaluate and reconsider diagnosis; initiate Participation in research trial
intravenous immune globu- treatment with rituximab§ if diagnosis is re-
lin is insufficient confirmed, recommend participation in a re-
search trial¶ if disease does not respond to
rituximab
* The use of these agents is based on experience but not on controlled studies. Azathioprine can be given at a dose of up
to 3 mg per kilogram, methotrexate at a dose of up to 20 mg per week, mycophenolate at a dose of 2000 to 3000 mg
per day, and cyclosporine at a dose of up to 300 mg daily. Intravenous cyclophosphamide (0.8 to 1 g per square meter
of body surface area) and oral tacrolimus (4–8 mg per day) may help patients with interstitial lung disease.
† All glucocorticoid-sparing agents are ineffective, either alone or in combination.
‡ In some patients, the dysphagia responds to intravenous immune globulin.
§ Efficacy has not been established with a controlled study, but the evidence of efficacy is compelling.
¶ Candidate agents include eculizumab, alemtuzumab, tocilizumab (anti–interleukin-6), anti–interleukin-17, and anti–
interleukin-1β.
of inflammatory signaling, such as interferon-γ– munosuppressant agent from the outset.6,61 In

receptor signaling.56 Compelling evidence suggests patients with rapidly worsening disease, it is pref-
that aging, abnormal proteostasis (the network erable to administer intravenous methylprednis-
controlling proteins),20 impaired autophagy, cell olone at a dose of 1000 mg per day for 3 to 5 days
stress induced by MHC class I or nitric oxide,21,57 before starting treatment with oral glucocorti-
long-standing inflammation, and proinflam- coids. After 3 to 4 weeks, prednisone is tapered,
matory cytokines such as interferon-γ and as dictated by the response of the disease to
interleukin-1β57,58 may cumulatively trigger or en- therapy, preferably by a switch from a daily dose
hance degeneration, leading to further accumu- to doses on alternate days60; however, if the ob-
lation of stressor molecules and misfolded pro- jective signs of increased strength and ability to
teins59 (Fig. 3). perform activities in daily living are absent at
that time, tapering is accelerated so that treat-
ment with a next agent can be started. A tactical
T r e atmen t of Der m at om yosi t is,
P olym yosi t is, a nd Necro t i zing error is the practice of “chasing” the creatine
Au t oim mune M yosi t is kinase level as a sign of response, especially in
patients who report a sense of feeling better but
Strategies for the treatment of the inflammatory not necessarily of feeling stronger. When the
myopathies are described in Table 2. Oral pred- strength improves, the serum creatine kinase level
nisone administered once daily after breakfast at drops, but a decrease in creatine kinase alone is
a dose of 1 mg per kilogram of body weight, up not a sign of improvement.60
to 100 mg per day, is the first-line drug for the For patients in whom glucocorticoids produce
treatment of dermatomyositis, polymyositis, and a response, azathioprine, mycophenolate mofetil,
necrotizing autoimmune myositis; this choice of methotrexate, or cyclosporine can be used em-
drug is based on experience but not on controlled pirically for glucocorticoid sparing.2-4,6,60,61 When
trials.1-6,60,61 Some clinicians prefer to add an im- interstitial lung disease is a coexisting condition,

cyclophosphamide or tacrolimus may be help- evaluated in an ongoing trial (EudraCT number,

ful.6,60,62 In patients with dermatomyositis, topi- 2012-005772-34). Overall, the long-term outcome
cal glucocorticoids or calcineurin inhibitors and of inflammatory myopathies has substantially
sunlight avoidance are recommended. When glu- improved, with a 10-year survival rate of more
cocorticoids fail to induce remission or in severe than 90%.72
and rapidly progressive cases, intravenous im-
mune globulin therapy (2 g per kilogram in di- T r e atmen t of Inclusion-Body
vided doses over a period of 2 to 5 consecutive M yosi t is
days) is appropriate.2-4,6,60,61 In a double-blind
study, intravenous immune globulin was found to Because of T-cell–mediated cytotoxic effects and
be effective in the treatment of refractory derma- the enhancement of amyloid-related protein ag-
tomyositis63; monthly infusions may be required gregates by proinflammatory cytokines in pa-
to maintain remission.60,63 In open-label trials, tients with inclusion-body myositis,21,57,58 immu-
intravenous immune globulin has also appeared nosuppressive agents have been tried as treatment
to be effective in the treatment of polymyositis for this disease subtype, but all have failed,
and necrotizing autoimmune myositis.6,60 Subcuta- probably because the disease starts long before
neous immune globulin has appeared to sustain patients seek medical advice, when the degen-
remission in small-scale, uncontrolled studies.64 erative cascade is already advanced.60 Glucocorti-
If the disease has not responded to glucocor- coids, methotrexate, cyclosporine, azathioprine,
ticoids and intravenous immune globulin, the and mycophenolate are ineffective, and although
patient should be reevaluated, and if there are some patients may initially have mild subjective
diagnostic uncertainties, a repeat muscle biopsy improvements when treated with one of these
should be considered. If the diagnosis is recon- agents,60,61 no long-term benefit is achieved.73 In-
firmed, biologic agents that have been approved travenous immune globulin has been found to be
for the treatment of other immune diseases may ineffective in controlled trials but may transiently
be considered as experimental treatment options.60 help some patients, especially those with dyspha-
These include rituximab (an anti-CD20 antibody), gia.74,75 Alemtuzumab may provide short-term sta-
which at a dose of 2 g (divided into two infu- bilization,76 but a controlled study is needed.
sions 2 weeks apart) seems effective in some Treatment with anakinra has also not been suc-
patients with dermatomyositis, polymyositis, or cessful.77 Trials targeting muscle-inhibiting TGF-β
necrotizing autoimmune myositis. In a placebo- molecules or muscle growth factors are in prog-
controlled study involving 200 patients, at week ress. Bimagrumab, an antibody that inhibits the
8 there was no difference between the placebo signaling of a TGF-β superfamily receptor, was
group and the rituximab group, and on the basis shown in a small-scale study to increase muscle
of the study design, the results were not signifi- volume after 8 weeks,78 which has prompted an
cant; however, at week 44, when all the patients ongoing controlled study (ClinicalTrials.gov num-
had received rituximab, 83% met the definition ber, NCT01925209). A small, controlled, proof-of-
of improvement.65 Patients with anti-Jo-1, anti- concept study of arimoclomol (ClinicalTrials.gov
Mi-2, or anti-SRP antibodies seem more likely to number, NCT00769860), an agent that up-regu-
have a response.66,67 Tumor necrosis factor inhibi- lates heat shock protein response and attenuates
tors (infliximab, adalimumab, and etanercept) are cell stress, has been completed; the drug had an
ineffective and may worsen or trigger disease.68 acceptable adverse-event profile, but whether there
Other biologics that may be considered as experi- were clinically meaningful benefits is still un-
mental treatment include alemtuzumab, which clear.79
is reportedly effective in polymyositis69; anti-com- At present, symptomatic therapies are the
plement C3 (eculizumab), which is effective in best option. For life-threatening dysphagia that
complement-mediated diseases and may be ef- is not responding to intravenous immune globu-
fective for the treatment of dermatomyositis and lin, cricopharyngeal dilation or myotomy may be
necrotizing autoimmune myositis; anti–interleu- considered. As with all inflammatory myopa-
kin-6 (tocilizumab)70 and anti–interleukin-1 re- thies, nonfatiguing resistance exercises and oc-
ceptor (anakinra),71 which have been effective in cupational and rehabilitation therapies are use-
anecdotal cases; anti–interleukin-17; and anti– ful to improve ambulation, prevent falling, avoid
interleukin-1β (gevokizumab), which is being disuse atrophy, and prevent joint contractures.80

Although the life expectancy of patients with zyme and lecture fees from Baxter and Octapharma. No other
potential conflict of interest relevant to this article was reported.
inclusion-body myositis is normal, most patients
Disclosure forms provided by the author are available with the
with end-stage disease require assistive devices full text of this article at NEJM.org.
such as a cane, walker, or wheelchair.23 I thank all the clinical and research fellows who participated
Dr. Dalakas reports having served on a data and safety moni- in my studies over many years, the numerous clinicians and
toring board for Baxter, serving on steering committees for scientists for their enormous contributions to the field, and all
Grifols/Talecris, Novartis, and Servier, and receiving consulting the patients who participated in my research and continue to
fees from Baxter, Therapath Laboratory, CSL Behring, and Gen- teach me about these diseases.
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Documento descargado de http://www.analesdepediatria.org el 16/09/2015.

An Pediatr (Barc). 2015;83(3):216.e1---216.e10

ASOCIACIÓN ESPAÑOLA DE PEDIATRÍA

Documento de Consenso SEIP-SERPE-SEOP sobre

Recibido el 8 de agosto de 2014; aceptado el 18 de agosto de 2014

PALABRAS CLAVE Resumen Se presenta el Documento de Consenso sobre etiopatogenia y diagnóstico de la

KEYWORDS SEIP-SERPE-SEOP Consensus Document on aetiopathogenesis and diagnosis of

216.e2 J. Saavedra-Lozano et al.

Tabla 2 Factores predisponentes que favorecen el desarro-

Infecciones osteoarticulares 216.e3

Situación de riesgo Bacterias

plasmocoagulasa negativo o Candida.

216.e4 J. Saavedra-Lozano et al.

Manifestaciones clínicas Estos niños tienen un elevado riesgo de presentar OmA y

Infecciones osteoarticulares 216.e5

Maniobras de detección ¿Qué valora?

Para la exploración de la zona sacroilíaca puede ser de Diagnóstico de la infección osteoarticular

216.e6 J. Saavedra-Lozano et al.

Tabla 5 Características del líquido articular

Infecciones osteoarticulares 216.e7

Sospecha infección osteoarticular

Sospecha artritis séptica Sospecha osteomielitis

Figura 1 Algoritmo diagnóstico de la infección osteoarticular.

216.e8 J. Saavedra-Lozano et al.

Tabla 6 Diagnóstico diferencial de monoartritis

Infecciones osteoarticulares 216.e9

Tabla 7 Resumen de recomendaciones y evidencia

216.e10 J. Saavedra-Lozano et al.

Dan L. Longo, M.D., Editor

Inflammatory Muscle Diseases

1734 n engl j med 372;18 nejm.org April 30, 2015

The New England Journal of Medicine

n engl j med 372;18 nejm.org April 30, 2015 1735

Criterion Dermatomyositis Polymyositis Necrotizing Autoimmune Myositis Inclusion-Body Myositis

The New England Journal of Medicine

fever, and “mechanic’s hands”

n engl j med 372;18 nejm.org April 30, 2015

Copyright © 2015 Massachusetts Medical Society. All rights reserved.

n engl j med 372;18 nejm.org April 30, 2015 1737

1738 n engl j med 372;18 nejm.org April 30, 2015

The New England Journal of Medicine

E Possible NO R M A L F A S CICLE D A M A GE D F A S CICLE S

C3a C3b Capillary

MAC ROP HAG E

n engl j med 372;18 nejm.org April 30, 2015 1739

lation is often prominent beyond the necrotic fi-

1740 n engl j med 372;18 nejm.org April 30, 2015

The New England Journal of Medicine

G B cells may serve as

n engl j med 372;18 nejm.org April 30, 2015 1741

1742 n engl j med 372;18 nejm.org April 30, 2015

The New England Journal of Medicine

Cell stress and fiber damage Autophagic

Figure 3. Proposed Mechanisms in Inclusion-Body Myositis.

n engl j med 372;18 nejm.org April 30, 2015 1743

Table 2. Treatment of Inflammatory Myopathies: A Step-by-Step Approach.

Treatment for Dermatomyositis, Polymyositis, Treatment for Inclusion-Body

of inflammatory signaling, such as interferon-γ– munosuppressant agent from the outset.6,61 In

1744 n engl j med 372;18 nejm.org April 30, 2015

The New England Journal of Medicine

cyclophosphamide or tacrolimus may be help- evaluated in an ongoing trial (EudraCT number,

n engl j med 372;18 nejm.org April 30, 2015 1745

1746 n engl j med 372;18 nejm.org April 30, 2015