Pediatric

DXA

technique

and

interpretation

This

article

reviews

dual

X-ray

absorptiometry

-LRB-

DXA

-RRB-

technique

and

interpretation

with

emphasis

on

the

considerations

unique

to

pediatrics

Specifically

the

use

of

DXA

in

children

requires

the

radiologist

to

be

a

clinical

pathologist

monitoring

the

technical

aspects

of

the

DXA

acquisition

a

statistician

knowledgeable

in

the

concepts

of

Z-scores

and

least

significant

changes

and

a

bone

specialist

providing

the

referring

clinician

a

meaningful

context

for

the

numeric

result

generated

by

DXA

The

patient

factors

that

most

significantly

influence

bone

mineral

density

are

discussed

and

are

reviewed

with

respect

to

available

normative

databases

The

effects

the

growing

skeleton

has

on

the

DXA

result

are

also

presented

Most

important

the

need

for

the

radiologist

to

be

actively

involved

in

the

technical

and

interpretive

aspects

of

DXA

is

stressed

Finally

the

diagnosis

of

osteoporosis

should

not

be

made

on

DXA

results

alone

but

should

take

into

account

other

patient

factors

Introduction

After

its

commercial

introduction

in

dual

energy

X-ray

absorptiometry

-LRB-

DXA

-RRB-

has

become

a

widely

available

and

clinically

useful

tool

in

the

evaluation

and

management

of

adult

bone

diseases

More

recently

its

utilization

in

the

pediatric

population

has

rapidly

increased

DXA

presents

unique

challenges

to

pediatric

radiologists

and

the

aim

of

this

article

is

to

review

the

technique

and

interpretation

of

DXA

Special

focus

is

on

the

issues

unique

to

pediatric

DXA

emphasizing

the

need

for

an

expanded

role

for

the

pediatric

radiologist

in

the

performance

and

interpretation

of

DXA

examinations

Is

the

result

of

a

DXA

examination

a

number

or

a

diagnosis

From

the

radiologist

's

perspective

it

is

both

making

it

different

from

all

other

imaging

studies

Like

many

laboratory

tests

the

DXA

examination

generates

a

numerical

result

The

radiologist

like

the

clinical

pathologist

must

be

knowledgeable

about

the

processes

by

which

that

number

is

obtained

and

must

ensure

that

meticulous

technique

is

used

-LSB-

-RSB-

Additionally

the

radiologist

must

be

knowledgeable

about

the

statistical

limitations

and

uses

of

a

numerical

result

For

example

he

or

she

must

be

familiar

with

the

precision

and

accuracy

of

the

technique

and

be

able

to

consult

regarding

the

least

significant

change

and

be

able

to

suggest

appropriate

follow-up

intervals

-LSB-

-RSB-

The

radiologist

must

also

interpret

the

study

in

terms

of

the

relevant

patient

factors

that

influence

the

numeric

result

These

factors

include

gender

ethnicity

height

weight

body

composition

and

physiologic

maturity

and

they

might

be

incorporated

in

the

interpretation

of

the

study

Therefore

the

result

of

a

DXA

examination

is

both

a

number

and

a

diagnosis

and

radiologists

should

be

expert

in

understanding

and

reporting

both

aspects

in

the

DXA

report

The

diagnosis

of

osteoporosis

should

not

be

made

on

DXA

results

alone

but

should

take

into

account

other

patient

factors

Additionally

the

radiologist

needs

to

be

aware

of

the

limitations

of

DXA

in

children

-LSB-

-RSB-

there

are

difficulties

in

scan

interpretation

because

DXA

is

an

areal

rather

than

a

volumetric

density

measurement

the

growing

skeleton

has

an

impact

on

follow-up

measurements

there

is

a

lack

of

consensus

regarding

the

patient

demographic

and

physiologic

factors

that

should

be

incorporated

into

normative

databases

and

there

is

yet

to

be

determined

a

prognostic

value

of

pediatric

DXA

with

regard

to

fracture

risk

or

peak

bone

mineral

density

-LRB-

BMD

-RRB-

-LSB-

-RSB-

Areal

vs.

volumetric

bone

mineral

density

As

in

all

radiologic

studies

DXA

relies

on

the

differential

absorption

of

X-rays

to

differentiate

tissues

of

different

radiographic

density

In

addition

DXA

can

quantify

-LRB-

in

grams

-RRB-

the

bone

mineral

content

-LRB-

BMC

-RRB-

at

various

body

sites

By

selecting

regions

of

interest

a

bone

area

-LRB-

BA

-RRB-

is

selected

with

units

of

centimeters

squared

-LRB-

The

abbreviation

BA

for

bone

area

should

not

be

mistaken

for

bone

age

-RRB-

BMD

is

measured

directly

for

each

pixel

in

the

region

of

interest

-LRB-

ROI

-RRB-

by

comparing

the

X-ray

attenuation

of

that

pixel

to

a

reference

standard

It

has

units

of

grams

per

centimeter

squared

This

value

is

multiplied

by

the

pixel

's

area

to

derive

the

BMC

of

that

pixel

with

units

of

grams

The

areas

of

all

the

pixels

in

the

ROI

are

summed

to

give

BA

Thus

BMD

BMC/BA

Unlike

other

density

measurements

the

DXA-derived

BMD

is

based

on

the

two-dimensional

projected

area

of

a

three-dimensional

structure

The

third

dimension

depth

can

not

be

accounted

for

directly

because

it

is

in

the

same

direction

as

the

X-ray

beam

Therefore

DXA-derived

BMD

is

an

areal

-LRB-

aBMD

-RRB-

rather

than

a

true

volumetric

-LRB-

vBMD

-RRB-

density

Because

the

third

dimension

is

unaccounted

for

problems

with

DXA-derived

BMD

can

arise

-LSB-

-RSB-

Specifically

smaller

bones

will

be

found

to

have

lower

aBMD

than

larger

bones

even

when

the

vBMD

is

the

same

-LRB-

Fig.

-RRB-

For

material

of

the

same

true

density

a

larger

cube

will

be

stronger

than

a

smaller

cube

Thus

in

giving

a

lower

aBMD

for

smaller

bones

when

compared

to

larger

bones

with

the

same

vBMD

an

aBMD

might

give

a

more

accurate

indication

of

bone

strength

relative

to

size

than

a

vBMD

Additionally

unlike

adult

patients

in

whom

the

bone

volume

does

not

change

over

time

a

child

's

bones

grow

over

time

and

the

growth

of

individual

bones

is

not

uniform

in

three

dimensions

Thus

errors

resulting

from

areal

measurements

of

BMD

might

be

introduced

with

DXA

and

can

make

comparison

of

follow-up

and

baseline

studies

more

challenging

to

interpret

in

pediatric

patients

-LSB-

-RSB-

Fig.

two

bones

of

known

BMD

the

DXA-derived

areal

BMD

will

be

higher

in

the

larger

bone

because

of

the

lack

of

accounting

for

the

true

volume

of

the

measured

bone

It

should

be

noted

that

the

larger

cube

will

be

stronger

than

the

smaller

cube

-LRB-

adapted

from

Carter

et

al.

-LSB-

-RSB-

with

permission

-RRB-

Technical

aspects

of

DXA

performance

Patient

positioning

and

ROI

selection

as

performed

by

the

technologist

require

precision

-LSB-

-RSB-

and

evaluation

by

the

radiologist

for

each

study

The

lumbar

spine

should

be

straight

and

centered

in

the

image

with

visualization

of

the

last

rib

pair

and

the

upper

sacrum

Artifacts

including

enteric

tubes

orthopedic

hardware

and

jewelry

should

be

excluded

from

the

image

if

possible

Vertebral

segments

with

overlying

artifacts

should

be

excluded

from

BMD

analysis

The

ROIs

are

generated

automatically

using

edge-detection

software

and

are

selected

for

the

to

vertebral

bodies

These

regions

should

include

the

entire

vertebral

body

with

a

minimum

of

adjacent

soft

tissue

-LRB-

Fig.

-RRB-

For

evaluation

of

the

hip

the

femoral

shaft

should

be

parallel

to

the

long

axis

of

the

image

with

only

a

small

amount

of

the

lesser

trochanter

visualized

When

using

the

manufacturer

's

provided

positioning

device

there

should

be

no

overlap

of

the

trochanters

and

the

femoral

neck

or

acetabulum

The

ROIs

include

the

femoral

neck

trochanter

intertrochanteric

and

total

hip

-LRB-

Fig.

-RRB-

The

region

of

lowest

femoral

neck

BMD

known

as

Ward

's

triangle

is

not

used

in

pediatric

DXA

analysis

and

often

use

of

the

total

hip

measurement

is

favored

over

the

other

subgroups

in

clinical

practice

because

of

its

higher

precision

than

the

subgroups

Whole-body

scanning

provides

total

body

BMC

and

BMD

but

also

allows

for

subregions

with

appropriately

drawn

ROIs

-LRB-

Fig.

-RRB-

Because

of

the

normally

low

BMD

in

young

children

software

analysis

is

modified

for

children

to

improve

edge

detection

of

lower-density

bone

Such

algorithms

have

been

validated

in

healthy

obese

and

chronically

ill

children

for

the

assessment

of

lumbar

BMD

-LSB-

-RSB-

The

adult

algorithm

significantly

overestimates

lumbar

BMD

when

compared

to

the

pediatric

low-density

algorithm

-LRB-

Table

-RRB-

because

lower-density

bone

pixels

will

be

excluded

using

the

adult

algorithm

-LSB-

-RSB-

It

is

suggested

that

normative

pediatric

data

be

collected

using

the

low-density

analysis

routinely

in

children

thus

allowing

meaningful

comparisons

of

patient

data

to

normal

data

and

that

the

DXA

report

indicate

which

algorithm

-LRB-

adult

or

pediatric

-RRB-

was

used

-LSB-

-RSB-

Fig.

images

a

AP

image

of

the

lumbar

spine

shows

regions

of

interest

from

to

The

bone

area

and

mineral

content

are

used

to

derive

the

bone

mineral

density

at

each

level

The

areal

density

is

based

on

the

bone

area

the

depth

dimension

is

not

directly

assessed

with

DXA

Note

transitional

lumbosacral

vertebral

body

b

AP

image

of

the

lumbar

spine

shows

regions

of

interest

from

to

AP

DXA

image

of

the

left

hip

shows

regions

of

interest

of

the

femoral

neck

greater

trochanter

and

total

hip

c

Total

body

scan

with

sub-regions

of

interests

for

trunk

extremities

and

headTable

of

pediatric

vs.

adult

software

analysis

on

bone

area

and

BMC

results

Total

body

DXA

from

a

patient

processed

using

pediatric

and

adult

software

Note

decreased

BA

-LRB-

-RRB-

and

BMC

-LRB-

g

-RRB-

but

increased

BMD

-LRB-

-RRB-

with

the

adult

technique

Low-density

portions

of

the

bone

are

included

using

the

pediatric

technique

and

thus

a

larger

BA

-LRB-

-RRB-

with

a

greater

BMC

-LRB-

g

-RRB-

are

obtained

but

the

BMD

-LRB-

-RRB-

is

lower

because

of

the

inclusion

of

low-density

bone

pixelsRegionPediatricAdultBA

-LRB-

-RRB-

BMC

-LRB-

g

-RRB-

BMD

-LRB-

-RRB-

BA

-LRB-

-RRB-

BMC

-LRB-

g

-RRB-

BMD

-LRB-

-RRB-

Left

Right

Left

Right

Thoracic

Lumbar

Left

Right

The

sites

selected

for

BMD

analysis

should

provide

a

robust

evaluation

of

the

patient

bone

density

status

If

technically

feasible

the

pediatric

DXA

examination

should

measure

lumbar

spine

and

total

body

BMD

-LSB-

-RSB-

The

manufacturers

normative

data

for

the

hip

in

preadolescents

are

limited

and

evaluation

of

the

hip

is

not

recommended

in

these

young

children

There

are

normative

DXA

data

for

the

adolescent

hip

especially

in

girls

-LSB-

-RSB-

and

for

these

patients

this

site

might

be

a

useful

addition

to

the

standard

examination

When

evaluating

group

data

of

normal

children

there

is

usually

close

correlation

of

BMD

between

the

lumbar

spine

and

hip

-LSB-

-RSB-

For

individuals

when

the

DXA

results

deviate

from

normal

there

is

less

concordance

between

these

two

sites

For

example

if

the

hip

Z

score

is

between

and

the

lumbar

Z-score

will

vary

an

average

of

less

than

SD

from

the

hip

score

As

the

hip

Z-score

decreases

to

the

lumbar

score

varies

on

average

SD

from

the

hip

Z-score

For

example

immobilized

or

paraplegic

children

might

have

preserved

lumbar

BMD

but

low

hip

BMD

If

evaluation

of

the

spine

and

hip

is

not

feasible

because

of

extensive

orthopedic

hardware

or

patient

positioning

issues

DXA

of

the

forearm

can

be

performed

However

there

are

few

normative

data

for

pediatric

forearm

studies

and

the

value

obtained

might

be

useful

only

when

compared

to

subsequent

studies

Because

of

its

reproducibility

and

lack

of

areal

density-related

errors

the

total

body

BMC

is

preferred

for

the

assessment

of

bone

status

by

some

clinicians

and

researchers

-LSB-

-RSB-

The

DXA

lumbar

ROI

will

not

include

the

thoracic

spine

However

the

identification

of

a

thoracic

body

compression

deformity

in

patients

with

osteoporosis

has

significant

prognostic

value

indicating

a

higher

risk

of

subsequent

vertebral

compression

fractures

Evaluation

of

thoracic

and

lumbar

vertebral

bodies

can

be

achieved

with

modern

DXA

scanners

-LRB-

Fig.

-RRB-

and

can

identify

thoracic

compression

fractures

that

would

have

been

otherwise

undiagnosed

Makitie

et

al.

-LSB-

-RSB-

found

compressive

thoracic

deformities

in

of

children

suspected

of

having

secondary

osteoporosis

who

were

studied

with

DXA

Of

these

children

had

normal

lumbar

DXA

and

the

demonstration

of

a

thoracic

compressive

deformity

was

thought

to

be

an

important

diagnostic

and

prognostic

finding

The

addition

of

vertebral

morphologic

assessment

might

be

an

important

adjunct

in

the

diagnosis

of

pediatric

osteoporosis

Fig.

thoracic

and

lumbar

spine

image

from

DXA

study

for

vertebral

morphology

Note

compressive

deformities

at

and

and

a

Schmorl

's

node

at

with

otherwise

normal

vertebral

morphology

of

the

lumbar

spine

DXA

requires

remarkably

low

radiation

doses

Using

manufacturers

data

the

effective

dose

for

lumbar

spine

and

whole-body

DXA

is

reported

to

be

μSv

-LSB-

-RSB-

This

is

less

than

the

dose

of

a

standard

PA

chest

radiograph

Scanning

times

are

now

less

than

min

for

the

spine

hip

or

forearm

and

less

than

min

for

the

total

body

Accuracy

precision

and

least

significant

change

DXA

provides

both

accurate

and

precise

bone

mineral

data

Accuracy

refers

to

how

close

a

measured

value

is

to

the

true

value

as

determined

by

a

gold-standard

technique

For

BMC

the

gold

standard

is

the

laboratory

assessment

of

ashed

bones

and

DXA

measurements

of

BMC

are

within

of

ashed

bone

measurements

-LSB-

-RSB-

Precision

is

a

measure

of

reproducibility

of

a

measurement

and

can

be

expressed

in

terms

of

coefficients

of

variation

-LRB-

CV

-RRB-

Both

short

and

long-term

precision

are

important

in

performing

DXA

examinations

Short-term

precision

reflects

both

the

imprecision

of

the

equipment

-LRB-

manufacturers

report

this

to

be

less

than

-RRB-

and

the

imprecision

resulting

from

variation

in

patient

positioning

and

motion

effects

-LRB-

typical

values

are

less

than

for

the

spine

up

to

for

the

hip

and

for

the

whole

body

-RRB-

-LSB-

-RSB-

This

component

varies

with

each

technologist

and

should

be

calculated

with

a

repeated

measures

procedure

-LSB-

-RSB-

Long-term

precision

is

a

measure

of

machine

drift

It

is

normally

well

below

and

the

radiologist

should

review

the

daily

quality

control

scans

of

phantoms

graphed

over

a

period

of

weeks

in

order

to

detect

this

-LSB-

-RSB-

Because

the

DXA

result

is

a

number

the

radiologist

must

be

aware

that

the

magnitude

of

change

required

to

be

statistically

significant

varies

with

the

precision

of

the

measurement

technique

This

is

expressed

in

terms

of

the

least

significant

change

-LRB-

LSC

-RRB-

and

is

equal

to

CV

for

the

confidence

limit

-LSB-

-RSB-

If

the

CV

was

then

a

change

from

the

baseline

measurement

of

would

be

required

for

it

to

be

considered

statistically

significant

The

LSC

can

also

be

used

to

suggest

the

timing

of

follow-up

measurements

i.e.

if

the

LSC

is

and

the

expected

annual

rate

of

change

in

the

BMC

or

BMD

is

a

follow-up

study

before

years

would

likely

result

in

a

value

not

statistically

significantly

different

from

the

baseline

The

annual

rates

of

change

in

BMC

and

BMD

vary

considerably

during

childhood

with

dramatic

acceleration

of

bone

accrual

during

the

early

pubertal

years

-LSB-

-RSB-

especially

in

females

-LSB-

-RSB-

The

annual

rates

of

change

for

early-stage

and

late-stage

adolescents

are

approximately

and

for

BMC

and

and

for

BMD

-LSB-

-RSB-

For

most

pediatric

conditions

follow-up

examinations

are

obtained

between

and

months

DXA

in

newborns

DXA

has

been

used

to

evaluate

bone

mineralization

in

newborns

and

young

infants

since

its

inception

as

a

clinical

tool

and

numerous

investigators

have

established

its

precision

and

accuracy

-LSB-

-RSB-

The

technique

has

a

high

degree

of

accuracy

even

in

preterm

low-birth-weight

neonates

with

a

slight

underestimation

of

BMC

of

approximately

-LSB-

-RSB-

The

high

precision

of

DXA

has

been

shown

in

neonates

with

CV

of

-LSB-

-RSB-

for

measurements

of

the

lumbar

spine

and

of

the

total

body

BMC

when

assessed

in

piglets

-LSB-

-RSB-

The

absorbed

dose

is

extremely

low

and

most

neonates

and

infants

can

be

imaged

with

gentle

immobilization

without

the

need

for

sedation

Normative

data

for

neonates

indicate

a

very

close

relationship

of

total

body

BMC

and

BA

with

weight

height

is

also

strongly

correlated

with

BMC

in

the

newborn

-LSB-

-RSB-

Koo

et

al.

-LSB-

-RSB-

found

weight

and

to

a

lesser

extent

body

length

but

not

gender

or

race

to

predict

total

body

BMC

BA

and

BMD

in

newborns

Additionally

body

mass

was

more

closely

correlated

with

BMC

and

BA

than

BMD

This

may

be

because

of

DXA-derived

BMD

is

areal

rather

than

volumetric

Last

the

proportional

contribution

to

total

body

BMC

from

each

subregion

-LRB-

head

trunk

and

upper

and

lower

extremities

-RRB-

is

maintained

across

gestational

ages

-LRB-

weeks

-RRB-

and

birth

weights

-LRB-

kg

-RRB-

with

only

slight

variation

-LSB-

-RSB-

Indications

for

pediatric

DXA

Despite

many

potential

uses

of

DXA

there

has

been

relatively

little

written

regarding

the

indications

for

DXA

in

children

The

International

Society

for

Clinical

Densitometry

has

suggested

that

any

child

being

treated

or

considered

for

treatment

of

osteoporosis

should

undergo

a

DXA

examination

-LSB-

-RSB-

The

National

Osteoporosis

Foundation

lists

the

following

indications

for

DXA

in

children

systemic

long-term

steroids

chronic

inflammatory

conditions

hypogonadism

prolonged

immobilization

osteogenesis

imperfecta

idiopathic

juvenile

osteoporosis

recurrent

low

trauma

fractures

and

apparent

osteopenia

on

radiographs

-LSB-

-RSB-

It

is

important

to

note

that

DXA

would

be

inappropriate

for

skeletal

pain

chronic

disease

and

traumatic

fractures

without

any

of

the

additional

risk

factors

listed

above

-LSB-

-RSB-

The

National

Institutes

of

Health

recommend

a

baseline

DXA

examination

for

patients

for

whom

systemic

corticosteroids

will

be

used

for

more

than

months

or

who

are

at

significant

risk

of

osteoporotic

fracture

-LSB-

-RSB-

These

guidelines

are

also

suggested

by

the

American

College

of

Rheumatology

-LSB-

-RSB-

The

American

College

of

Radiology

has

listed

DXA

of

the

lumbar

spine

and

hip

as

highly

appropriate

for

pediatric

patients

with

a

significant

risk

factor

for

osteoporosis

-LSB-

-RSB-

Recommendations

from

other

subspecialty

societies

have

been

slow

in

coming

Neither

the

Society

for

Pediatric

Radiology

nor

the

American

Academy

of

Pediatrics

has

made

recommendations

regarding

pediatric

DXA

Pediatric

DXA

interpretation

As

with

other

laboratory

tests

the

numeric

value

reported

is

meaningless

without

comparison

to

the

appropriate

normal

controls

After

comparison

is

made

the

reported

value

is

given

as

a

percentile

or

a

standard

deviation

score

the

Z-score

A

Z-score

of

zero

is

equivalent

to

the

mean

and

Z-scores

of

and

are

equivalent

to

values

one

standard

deviation

below

and

standard

deviations

above

the

mean

respectively

The

T-score

-LRB-

comparison

of

the

current

Z-score

with

peak

adult

BMD

-RRB-

is

used

in

adult

interpretation

of

DXA

but

should

not

be

included

in

the

pediatric

DXA

report

-LSB-

-RSB-

Because

the

T-score

is

a

measure

of

bone

density

loss

since

early

adulthood

its

use

in

children

whose

BMD

has

yet

to

peak

will

always

yield

a

low

result

Because

the

World

Health

Organization

's

DXA-based

definitions

of

osteopenia

and

osteoporosis

are

in

terms

of

T-scores

T

and

T

respectively

-LSB-

-RSB-

a

different

terminology

is

needed

for

pediatric

patients

It

is

recommended

that

the

phrase

low

bone

density

be

used

in

DXA

reports

-LSB-

-RSB-

Some

clinicians

and

researchers

use

the

terms

osteopenia

and

osteoporosis

in

children

when

Z-scores

are

less

than

and

respectively

It

is

important

to

note

that

the

diagnosis

of

osteoporosis

should

not

be

made

on

DXA

results

alone

but

should

take

into

account

other

patient

factors

Much

of

the

research

in

pediatric

DXA

has

focused

on

determining

which

factors

most

influence

BMD

and

should

be

accounted

for

in

the

development

of

normative

pediatric

datasets

The

factors

age

gender

ethnicity

and

physiologic

maturity

level

have

been

extensively

studied

and

are

included

in

most

current

normative

datasets

provided

by

the

major

DXA

manufacturers

Some

of

the

earliest

reports

indicate

the

influence

of

age

on

BMD

values

and

several

authors

have

presented

normal

data

accounting

for

age

-LSB-

-RSB-

The

effect

that

age

has

on

BMD

is

largely

related

to

the

increase

in

frame

size

that

occurs

with

increasing

chronologic

age

Increasing

height

and

weight

strongly

correlate

with

increasing

BMC

and

BMD

The

changes

in

height

and

weight

are

most

pronounced

during

the

pubertal

growth

spurt

BMD

increases

rapidly

during

early

puberty

-LSB-

-RSB-

but

because

the

age

of

pubertal

onset

is

quite

variable

physiologic

maturity

has

a

stronger

influence

on

BMD

than

age

Several

authors

have

included

Tanner

stage

or

gynecologic

age

as

a

primary

factor

in

their

normative

datasets

-LSB-

-RSB-

Weight

is

an

important

factor

influencing

BMD

for

multiple

reasons

-LSB-

-RSB-

and

has

been

included

in

normal

datasets

-LSB-

-RSB-

Ethnicity

has

been

determined

to

be

important

in

the

analysis

of

BMD

results

with

black

children

showing

significantly

higher

BMD

values

than

non-black

children

-LSB-

-RSB-

Multiple

factors

are

thought

to

account

for

this

including

increased

cross-sectional

area

in

the

axial

skeleton

and

thicker

trabecula

in

cancellous

bone

-LSB-

-RSB-

Lifestyle

and

anthropometric

factors

might

also

play

a

role

-LSB-

-RSB-

There

are

numerous

published

pediatric

normative

datasets

many

of

which

are

summarized

in

Table

These

datasets

have

been

developed

using

a

variety

of

scanners

and

processing

software

and

are

based

on

various

combinations

of

demographic

and

physiologic

patient

variables

Rather

than

simplifying

pediatric

DXA

interpretation

the

sheer

number

of

available

normal

databases

has

made

DXA

interpretation

complex

confusing

and

at

times

erroneous

-LSB-

-RSB-

To

report

the

numeric

result

generated

from

the

manufacturer

's

automated

processing

without

consideration

of

factors

specific

to

the

patient

being

studied

is

unacceptable

This

often

will

lead

to

misdiagnoses

and

can

result

in

inappropriate

therapy

-LSB-

-RSB-

In

fact

the

diagnosis

of

osteoporosis

in

a

child

based

on

a

DXA

result

is

often

a

misinterpretation

of

the

scan

data

Gafni

and

Baron

-LSB-

-RSB-

found

this

to

be

the

case

in

more

than

half

of

the

pediatric

patients

referred

to

them

with

the

diagnosis

of

osteoporosis

The

most

common

causes

for

misdiagnosis

were

the

use

of

T-scores

inappropriate

normative

datasets

inadequate

ROIs

and

inattention

to

short

stature

Table

pediatric

DXA

databases

-LRB-

C/B/H

A/O

Caucasian/black/Hispanic

Asian/other

GA

gestational

age

-LRB-

L

-RRB-

longitudinal

study

SA

surface

area

-RRB-

ReferenceYearScannerNo

of

patients

-LRB-

M/F

-RRB-

Age

rangeEthnicity

-LRB-

C/B/H

A/O

-RRB-

weight

height

SALumbar

BMD

and

monthsGA

weight

height

SALumbar

BMD

and

weeksWeightTotal

BMD

BMC

and

Tanner

stageLumbar

yearsWeightLumbar

yearsGender

Tanner

stageTotal

BMC

and

years

-LRB-

L

-RRB-

Tanner

stageTotal

BMD

BMC

and

years

-LRB-

L

-RRB-

ageLumbar

BMD

and

apparent

BMD

or

total

BMC

fat

and

lean

body

massGender

Tanner

stageLumbar

BMD

and

apparent

BMD

or

total

BMD

and

ageTotal

BMC

and

BAGender

heightTotal

BAGender

total

BMCTotal

FBup

to

yearsGender

age

Lumbar

total

hip

and

total

Tanner

stage

or

age

Lumbar

BMC

BA

and

BMD

femoral

neck

years

-LRB-

L

-RRB-

ageLumbar

and

total

BMC

and

BMDFemoral

neck

BMC

and

years

-LRB-

L

-RRB-

age

ethnicityLumbar

femoral

neck

and

total

hip

BMD

and

BMADTotal

BMD

and

weight

ethnicity

Lumbar

and

femoral

neck

BMD

femoral

neck

apparent

years

-LRB-

L

-RRB-

stage

age

Lumbar

femoral

neck

trochanter

and

forearm

BMC

and

DPX

height

or

ageTotal

lean

body

mass

and

total

BMC/lean

body

massaFurther

data

available

at

data

available

at

As

with

any

other

radiologic

study

a

methodical

evaluation

of

the

results

should

be

undertaken

in

order

to

minimize

the

risk

of

misdiagnosis

The

radiologist

needs

to

review

all

input

data

including

patient

age

gender

ethnicity

weight

height

and

Tanner

stage

-LRB-

if

provided

-RRB-

Patient

positioning

should

be

evaluated

and

the

ROIs

need

to

be

analyzed

for

artifact

and

appropriateness

Comparison

should

be

made

with

previous

studies

to

ensure

consistency

of

positioning

and

ROI

selection

In

addition

changes

in

patient

height

weight

and

Tanner

stage

should

be

noted

After

these

steps

have

been

taken

interpretation

of

the

numeric

result

is

performed

An

appropriate

database

for

comparison

purposes

is

selected

Ideally

this

is

based

on

data

generated

locally

using

the

same

equipment

and

technologists

but

this

is

rarely

possible

Normative

data

provided

by

the

DXA

manufacturers

can

be

used

but

historically

these

datasets

do

not

include

the

parameters

currently

thought

to

be

most

important

for

interpretation

At

a

minimum

patient

body

size

-LRB-

height

and

weight

-RRB-

and

physiologic

maturity

-LRB-

Tanner

stage

gynecologic

or

bone

age

-RRB-

should

be

factors

included

in

the

normative

dataset

Ethnicity

and

gender

are

also

frequently

included

in

the

generation

of

normative

data

and

are

generally

thought

to

affect

BMD

significantly

Table

summarizes

a

large

number

of

normal

databases

that

can

be

used

to

best

match

the

patient

scan

to

be

analyzed

More

complex

and

scientifically

rigorous

analyses

of

the

BMD

result

have

been

suggested

Molgaard

et

al.

-LSB-

-RSB-

described

a

three-step

analysis

of

BMD

Bone

length

is

categorized

as

short

or

long

by

assessing

the

patient

's

height

for

age

Height

is

highly

correlated

with

BMC

-LSB-

-RSB-

and

thus

needs

to

be

accounted

for

especially

when

BMD

Z-score

is

abnormal

-LRB-

Z

-RRB-

Bone

width

is

categorized

as

thin

or

thick

by

assessing

BMC

for

height

Last

bone

mineralization

is

categorized

with

assessment

of

BMC

for

BA

The

first

step

takes

into

account

height

because

of

its

profound

effect

on

BMC

taller

children

will

have

a

higher

bone

content

However

bone

width

is

also

important

in

determining

bone

content

thus

the

second

step

accounts

for

this

The

last

step

is

often

the

only

step

performed

by

many

radiologists

with

reporting

of

BMC

for

BA

which

by

definition

is

BMD

Height

for

age

can

be

assessed

using

standard

growth

charts

corrected

for

age

gender

and

ethnicity

Percentile

rankings

can

be

easily

converted

to

a

Z-score

-LSB-

-RSB-

Bone

area

for

height

tables

are

available

for

select

groups

but

normative

data

for

all

pediatric

patients

need

to

be

developed

Using

this

three-step

analysis

Molgaard

and

Michaelsen

-LSB-

-RSB-

found

that

the

causes

for

low

BMC

might

be

various

combinations

of

factors

such

as

short

stature

and

thin

bones

as

in

children

with

cystic

fibrosis

or

short

stature

and

reduced

mineralization

as

in

children

with

milk

allergy

BMC

might

be

normal

despite

short

stature

in

the

presence

of

wide

bones

as

in

children

with

previously

treated

leukemia

In

summary

an

abnormal

BMD

Z-score

should

lead

to

evaluation

of

confounding

patient

factors

that

influence

BMD

including

height

weight

and

physiologic

maturity

before

a

diagnosis

of

low

bone

density

is

made

Until

the

manufacturers

databases

sufficiently

account

for

the

physiologic

factors

that

most

impact

BMD

results

normative

data

derived

locally

or

from

the

medical

literature

should

be

used

in

pediatric

DXA

interpretation

The

report

should

include

the

DXA

equipment

and

software

algorithm

used

-LRB-

pediatric

or

adult

low

bone

density

or

standard

-RRB-

the

source

of

the

normative

reference

data

the

Z-score

-LRB-

not

the

T-score

-RRB-

and

an

impression

giving

a

clinical

context

for

the

result

The

diagnosis

of

low

bone

density

does

not

rest

solely

on

the

DXA

numeric

result

and

the

report

should

indicate

which

patient

factors

were

incorporated

into

the

final

impression

A

specimen

DXA

report

and

the

examination

protocol

from

Columbus

Children

's

Hospital

are

given

in

Appendix

Bone

growth

over

time

and

changes

in

BMD

As

mentioned

previously

bone

size

affects

the

DXA

aBMD

result

Changes

in

bone

size

over

time

as

occur

in

normal

pediatric

development

confound

DXA

interpretation

This

is

one

of

the

major

limitations

in

the

use

of

pediatric

DXA

On

both

follow-up

studies

when

the

child

's

data

are

compared

to

prior

results

as

well

as

when

the

child

's

DXA

values

are

compared

to

normative

values

the

effect

of

bone

size

needs

to

be

accounted

for

These

problems

could

be

avoided

at

least

in

part

if

a

true

volumetric

BMD

were

available

with

DXA

As

this

is

not

possible

with

current

DXA

technology

investigators

have

attempted

to

account

for

the

effect

of

bone

volume

on

the

DXA

result

and

minimize

the

effect

the

growing

skeleton

has

on

the

BMD

value

-LSB-

-RSB-

Katzman

et

al.

-LSB-

-RSB-

estimated

the

volume

of

the

lumbar

vertebral

bodies

assuming

it

to

be

a

cube

using

this

formula

apparent

lumbar

BMD

-LRB-

BMAD

-RRB-

Kroger

et

al.

-LSB-

-RSB-

suggested

a

volumetric

correction

based

on

the

assumption

that

the

vertebral

body

is

a

cylinder

using

this

formula

BMAD

-LRB-

BMC

-RRB-

-LRB-

-LSB-

π

-LCB-

bone

width

-RCB-

-RSB-

-RRB-

This

correction

can

also

be

applied

to

the

femoral

shaft

and

neck

-LSB-

-RSB-

These

corrections

do

not

fully

account

for

changes

over

time

in

lumbar

BMD

but

do

eliminate

age

and

height

dependence

of

BMD

at

the

hip

A

different

approach

has

been

to

not

evaluate

BMD

at

all

but

to

measure

BMC

only

because

it

is

determined

with

greater

accuracy

and

precision

than

BMD

-LSB-

-RSB-

In

an

effort

to

incorporate

the

fundamental

relationship

between

the

mechanical

stress

a

bone

experiences

through

muscle

action

and

its

mineral

content

Hogler

et

al.

-LSB-

-RSB-

and

Crabtree

et

al.

-LSB-

-RSB-

used

DXA

to

assess

BMC

and

proposed

algorithms

that

focus

on

the

evaluation

of

lean

total

body

mass

-LRB-

LTM

-RRB-

with

respect

to

height

and

BMC

They

found

LTM

explains

greater

than

of

the

variation

in

total

body

BMC

in

boys

and

girls

By

incorporating

LTM/height

and

height/age

into

the

DXA

interpretation

patients

could

be

grouped

as

being

normal

or

having

a

primary

secondary

or

mixed

bone

defect

For

example

the

diagnosis

of

low

BMD

for

age

might

be

a

result

of

smaller

bones

and

not

osteopenia

Hogler

et

al.

-LSB-

-RSB-

found

children

with

growth

hormone

deficiency

to

be

short

for

their

age

-LRB-

low

height/age

ratio

-RRB-

but

to

have

a

normal

amount

of

bone

adaptation

-LRB-

BMC

-RRB-

for

the

muscle

force

-LRB-

LTM

-RRB-

The

BMC/LTM

ratio

for

these

children

is

normal

In

contrast

children

with

anorexia

nervosa

with

normal

height

had

low

LTM

and

also

low

BMC/LTM

ratios

Their

low

BMD

for

age

was

a

result

of

decreased

muscle

loading

on

bone

-LRB-

a

secondary

bone

defect

with

low

LTM/height

-RRB-

and

decreased

mineralization

for

the

level

of

muscle

loading

present

-LRB-

a

primary

defect

with

low

BMC/LTM

-RRB-

This

indicated

that

a

mixed

defect

caused

their

low

BMD

for

their

age

In

summary

smaller

bones

will

have

lower

aBMD

than

larger

bones

as

measured

with

DXA

even

when

the

vBMD

is

the

same

because

of

limitations

of

the

areal

bone

density

technique

Attempts

to

correct

for

or

to

circumvent

this

limitation

have

been

proposed

and

show

promise

in

improving

DXA

interpretation

and

our

understanding

of

bone

physiology

Clinical

case

studies

The

following

case

studies

are

examples

of

common

clinical

indications

for

DXA

in

pediatrics

and

illustrate

the

principles

used

at

Columbus

Children

's

Hospital

in

DXA

interpretation

Patient

was

a

white

female

with

nutritional

rickets

and

multiple

fractures

following

minimal

trauma

She

presented

for

a

baseline

study

and

was

Tanner

stage

and

weighed

kg

Her

lumbar

BMD

was

Using

our

normal

database

that

corrects

for

Tanner

stage

and

weight

-LSB-

-RSB-

the

patient

's

lumbar

BMD

was

far

below

the

first

percentile

-LRB-

Z-score

was

much

less

than

-RRB-

The

manufacturer

's

database

-LRB-

which

is

based

in

part

on

the

data

from

reference

-RRB-

yielded

a

Z-score

of

The

total

body

BMC

was

g

with

a

Z-score

of

-LSB-

-RSB-

The

patient

was

reported

as

having

markedly

reduced

lumbar

bone

density

and

reduced

total

body

BMC

Patient

was

a

black

female

with

lupus

On

baseline

DXA

the

lumbar

BMD

was

equivalent

to

a

Z-score

of

using

our

local

database

and

was

considered

to

be

a

high

normal

value

for

a

and

Tanner

stage

patient

The

total

body

BMC

was

g

equivalent

to

a

Z-score

of

-LSB-

-RSB-

and

was

also

thought

to

be

a

high

normal

value

During

the

next

months

she

was

treated

with

corticosteroids

and

gained

kg

and

progressed

to

Tanner

stage

On

follow-up

DXA

the

lumbar

BMD

was

This

value

corresponds

to

the

percentile

and

a

Z-score

of

-LSB-

-RSB-

Thus

she

had

a

slight

decrease

in

her

lumbar

BMD

value

at

a

time

when

rapid

bone

mineral

accrual

would

be

expected

-LSB-

-RSB-

This

was

made

evident

by

the

rather

marked

decrease

in

her

Z-score

from

to

Her

total

body

BMC

was

unchanged

but

the

Z-scores

also

decreased

substantially

Patient

was

a

white

female

with

Turner

syndrome

and

of

small

stature

-LRB-

cm

first

percentile

Z-score

-RRB-

Her

lumbar

BMD

was

equivalent

to

the

eighth

percentile

-LRB-

Z-score

-RRB-

for

Tanner

stage

and

weight

kg

-LSB-

-RSB-

It

should

be

noted

that

the

manufacturer

's

normal

database

yielded

a

lumbar

BMD

Z-score

of

but

it

did

not

take

into

account

height

or

weight

The

low

lumbar

BMD

Z-score

was

likely

a

result

of

the

patient

's

short

stature

-LRB-

low

height

Z-score

-RRB-

The

weight

correction

in

our

normal

database

partially

accounted

for

her

short

stature

and

gave

a

more

meaningful

interpretation

of

the

numeric

DXA

result

This

patient

's

bone

age

was

years

-LRB-

Z-score

-RRB-

and

using

this

rather

than

her

chronologic

age

-LRB-

years

-RRB-

with

the

manufacturer

's

normal

database

would

result

in

a

Z-score

of

This

value

would

better

reflect

the

patient

's

actual

bone

status

Because

our

database

corrects

for

weight

and

Tanner

stage

each

patient

is

weighed

and

has

a

Tanner

stage

determination

made

by

the

referring

clinician

prior

to

the

DXA

study

Thus

we

do

not

use

the

patient

's

bone

age

in

DXA

interpretation

Final

recommendations

Pediatric

radiologists

need

to

assume

a

more

prominent

role

in

DXA

performance

interpretation

and

research

They

require

expertise

with

DXA

as

a

laboratory

procedure

a

numeric

result

and

a

clinical

diagnostic

examination

The

radiologist

must

be

a

clinical

pathologist

closely

supervising

the

acquisition

of

the

DXA

study

with

assessment

of

quality

control

data

as

well

as

the

clinical

images

The

radiologist

must

be

a

statistician

understanding

the

principles

of

least

significant

change

and

the

relationship

of

standard

deviation

scores

and

percentile

rankings

The

radiologist

must

also

be

a

bone

specialist

providing

a

meaningful

context

for

DXA

translating

the

numeric

value

to

a

clinically

useful

result

As

always

pediatric

radiologists

must

be

children

's

health

advocates

by

ensuring

the

appropriate

clinical

use

of

DXA

as

well

as

actively

participating

in

research

efforts

B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O


Rituximab therapy for juvenile-onset systemic lupus erythematosus Rituximab -LRB- RTX -RRB- , an anti-CD20 monoclonal antibody , has been proposed for use in the therapy of systemic lupus erythematosus -LRB- SLE -RRB- . We present the initial long-term experience of the safety and efficacy of rituximab for treatment of SLE in children . Eighteen patients -LRB- mean age 14 ± 3 years -RRB- with severe SLE were treated with rituximab after demonstrating resistance or toxicity to conventional regimens . There was a predominance of female -LRB- 16/18 -RRB- and ethnic African -LRB- 13/18 -RRB- patients . All had lupus nephritis -LSB- World Health Organization -LRB- WHO -RRB- classes 3 -- 5 -RSB- and systemic manifestations of vasculitis . Clinical disease activity of the SLE was scored with the SLE-disease activity index 2K -LRB- SLEDAI-2K -RRB- . Patients were followed-up for an average of 3.0 ± 1.3 years -LRB- range 0.5 to 4.8 years -RRB- . B-cell depletion occurred within 2 weeks in all patients and persisted for up to 1 year in some . Clinical activity scores , double-stranded DNA -LRB- dsDNA -RRB- antibodies , renal function and proteinuria -LSB- urine protein to creatinine ratio -LRB- Upr/cr -RRB- -RSB- improved in 93 % of the patients . Five patients required multiple courses of RTX for relapse , with B-cell repopulation . One died of infectious endocarditis related to severe immunosuppression . In conclusion , our data support the efficacy of rituximab as adjunctive treatment for SLE in children . Although rituximab was well tolerated by the majority of patients , randomized controlled trials are required to establish its long-term safety and efficacy . Introduction Systemic lupus erythematosus -LRB- SLE -RRB- in children is known to carry a worse prognosis than in adults , especially in those of African and Hispanic ethnicity -LSB- 1 , 2 -RSB- . Although treatment protocols for proliferative lupus nephritis have evolved during the past two decades , pediatric regimens have been center based and selectively derived from adult protocols -LSB- 3 -RSB- . These protocols primarily include cyclophosphamide -LRB- CYC -RRB- , which carries long-term toxicities related to malignancy and gonadal dysfunction -LSB- 4 -RSB- . Most recently , B-lymphocyte function has been recognized as a major component in the pathogenesis of autoimmune diseases -LSB- 5 -RSB- . Rituximab -LRB- RTX -RRB- , a chimeric monoclonal antibody directed against CD20 lymphocytes -LRB- commonly called B-cells -RRB- , was developed as a primary treatment against B-cell lymphoma -LSB- 6 -RSB- and is now approved for use in the treatment of rheumatoid arthritis -LSB- 7 -RSB- . Although clinical trials of the use of RTX in adults with SLE are substantial and ongoing -LSB- 8 -RSB- , studies in children have been limited -LSB- 9 , 10 -RSB- . A collaborative retrospective and uncontrolled multicenter experience from Europe reported mixed results -LSB- 11 -RSB- . Unfortunately , that study failed to use a single protocol , and many patients were treated concurrently with more toxic medications , which made safety analysis unreliable -LSB- 11 -RSB- . The purpose of our study was to determine the safety and efficacy of RTX therapy in the treatment of children with severe SLE . Over the course of 7 years , we retrospectively assessed the indications and responses to RTX therapy in a cohort of children with active SLE that was refractory to conventional therapies or who had clinical indications prohibiting the use of more toxic immunosuppressant drugs . Patients and methods A retrospective analysis was performed on a cohort of 51 patients diagnosed with SLE and lupus nephritis who received their care at Holtz Children 's Hospital , University of Miami Miller School of Medicine , between January 1996 and June 2007 . The study was approved by the institutional review board , with waiver of consent authorization , and all subjects were assured anonymity in compliance with the Health Insurance Portability and Accountability Act -LRB- HIPAA -RRB- . The medical records were reviewed for patients ' demographic characteristics , age at diagnosis , prior and current medical treatments , type of lupus nephritis and serologic and clinical response to therapy . Children were considered eligible for inclusion in the analysis if they fulfilled the following criteria : -LRB- 1 -RRB- American College of Rheumatology -LRB- ACR -RRB- criteria for the diagnosis of SLE -LSB- 12 -RSB- ; -LRB- 2 -RRB- age < 16 years at the time of diagnosis of SLE ; -LRB- 3 -RRB- treatment with the anti-CD20 monoclonal antibody , rituximab , during the observation period from January 2000 through October 2007 . Clinical protocol Rituximab -LRB- RTX -RRB- was administered weekly for two to four doses . The initial dose was 188 mg/m2 , infused over 4 h. Subsequent doses were 375 mg/m2 per dose , infused over 6 h to 8 h. Premedication initially consisted of diphenhydramine and acetaminophen , administered 30 min before the rituximab infusion . However , mild infusion reactions , including pruritis , nausea and emesis , resulted in our adding hydrocortisone 50 -- 100 mg intravenously 30 min prior to each infusion . Lymphocyte subsets were assayed before and after each course of RTX therapy at 1 - to 3-month intervals . This included B cells assayed as CD19 + lymphocytes and T-cells assayed as CD4 and CD8 lymphocytes as total and percent of the total lymphocyte cell count . The serum immunoglobulin levels were measured every 1 to 6 months prior to and after the course of RTX . Adverse events were recorded from the time of the first infusion until 1 year following the treatment course . Lupus disease activity index and serology Clinical and biological parameters were assessed prior to the RTX infusion course , at 1 - to 3-month intervals thereafter . The clinical disease activity was scored with the SLE-disease activity index 2K -LRB- SLEDAI-2K -RRB- , which has a maximum activity score of 105 -LSB- 13 -RSB- . Laboratory evaluations included serum complement components -LRB- C3 and C4 -RRB- and anti-double stranded DNA -LRB- Anti-dsDNA -RRB- antibody and anti-nuclear antibody -LRB- ANA -RRB- . Lupus nephritis and renal disease activity Renal biopsies were classified according to the new proposed modifications of the World Health Organization -LRB- WHO -RRB- classifications -LSB- 14 -RSB- . Three patients were treated at the time they were on hemodialysis for extra-renal manifestations of SLE . For those patients not on dialysis , degree of proteinuria and renal function were assessed in response to RTX therapy . Degree of proteinuria was determined by the random urine protein to creatinine ratio -LRB- Upr/cr -RRB- in milligrams per milligram -LRB- mg/mg -RRB- , with normal < 0.2 and nephrotic range > 1.0 -LSB- 15 , 16 -RSB- . Serum albumin -LRB- Salb -RRB- was assayed as an indirect measure of the nephrotic syndrome . Serum creatinine -LRB- Scr -RRB- was assayed , and an estimation of glomerular filtration rate -LRB- eGFR -RRB- was derived by the height index formula of Schwartz , expressed as milliliters per minute per 1.73 meters squared -LRB- ml/min per 1.73 m2 -RRB- -LSB- 17 -RSB- . Complete renal remission was defined as normalization of Upr/cr and eGFR . Partial remission was defined as > 50 % decline in Upr/cr . All serum and urine chemical analyses and immunoassays were performed in the central hospital clinical laboratory or the Quest referral laboratories . Statistical methods All data sets were analyzed for Gaussian distribution using the D'Agostino -- Pearson omnibus test for normality . The data were calculated into average values at baseline and at 2 months , 4 months , and 6 months after initiation of treatment . Variables at baseline , during and after the treatment were compared by the Wilcoxon matched-pairs signed-ranks test . Differences in parameters between the 2 independent groups were analyzed using Mann-Whitney and the Friedman test with Dunn 's multiple comparisons post tests for repeated measures of nonparametric data . P values of less than 0.05 were considered significant . All results are expressed as mean ± standard deviation -LRB- SD -RRB- . Results Patients ' demographics During the period of observation 18 patients were treated with RTX for at least one course of two to four doses . There were 16 female patients and two male patients . Mean age at the time of diagnosis of SLE was 10.7 ± 2.5 years -LRB- range 7 to 14 years -RRB- . Mean duration of disease prior to treatment with RTX was 3.1 ± 2.5 years -LRB- range 2 months to 8 years -RRB- . Age at the time of first RTX treatment was 14.2 ± 3.3 years , and current age at the time of this report was 17 ± 5.0 years . All patients had clinical evidence of lupus nephritis . Individual patient demographics , clinical manifestations of SLE and indications for rituximab therapy for patients not on hemodialysis are shown in Table 1 . All patients received concurrent therapy with low-dose corticosteroids -LRB- CSs -RRB- and hydroxychloroquine -LRB- HCQ -RRB- . Sixteen patients had failed or had suffered toxic effects from multiple courses of intravenous therapy with cyclophosphamide -LRB- CYC -RRB- and corticosteroids . Treatment with RTX included concurrent or subsequent treatment with maintenance doses of mycophenolate mofetil -LRB- MMF -RRB- or azathioprine -LRB- AZT -RRB- similar to recently published adult protocols -LSB- 18 -RSB- . Table 1Patients ' baseline characteristics , indications for rituximab treatment , and clinical course -LRB- F female , M male , H Hispanic , B Black , HT hypertension , CYC cyclophosphamide , CyA cyclosporine A , AZT azathioprine , MMF mycophenolate mofetil , IVIG intravenous therapy with gamma globulin , CS corticosteroids , HXQ hydroxychloroquine , FR full remission , PR partial remission -RRB- PatientGenderAge at diagnosis -LRB- years -RRB- RaceIndication for rituximabNephritis classPrevious and/or concurrent therapiesaUpr/cr -LRB- mg/mg -RRB- OutcomeBefore RTXAfter RTX1F12 .0 BNephritis , serositis , Coomb 's -LRB- + -RRB- anemia , CYC-toxicityIVCYC , MMF13 .00.1 FR2M10 .0 WNephritis , serositis , CS toxicityIVCYC , MMF2 .10.6 PR3F11 .0 BNephritis , serositis , Coomb 's -LRB- + -RRB- anemia , CYC - toxicity sepsisIVCYC , MMF4 .01.7 PR4F8 .0 HPulmonary HT , nephritis , Coomb 's -LRB- + -RRB- anemiaIV-VCYC , MMF , IVIG2 .60.2 FR5F12 .0 BOphthalmic vasculitis , nephritisIV-VCYC , AZT0 .40.1 FR6F14 .0 BNephritis , Coomb 's -LRB- + -RRB- anemia , CS toxicityNACYC , AZT , MMF , IVIG0 .60.3 PR7F12 .0 BNephritis , serositis , CYC-toxicity sepsisIV-VCYC , AZT , MMF , IVIG2 .6 NADied8F12 .0 BNephritis , serositis , Coomb 's -LRB- + -RRB- anemiaIVCYC , AZT , IVIG3 .61.9 PR9F14 .0 BNephritis , serositis , ataxia , miliary tuberculosisIIIIVIG1 .70.2 FR10F7 .0 HNephritis , serositis , arthritis , CYC-toxicity sepsisIVCYC , MMF , IVIG3 .00.7 PR11F12 .8 HNephritis , serositis , arthritis , obesityVMMF9 .70.2 FR12F7 .0 BNephritis , thrombocytopenia , CYC toxicityIV-VCYC , AZT , MMF , IVIG , CyA5 .40.2 FR13F7 .0 BNephritis , Coomb 's -LRB- + -RRB- anemia , skin vasculitisIVMMF1 .50.2 FR14M12 .5 HNephritis , serositis , arthritis , CYC-toxicity sepsisIIICYC , MMF , IVIG2 .30.8 PR15F13 .0 BNephritis , arthritis , skin vasculitis , Coomb 's -LRB- + -RRB- anemiaIVCYC , MMF , IVIG6 .80.9 PRaAll patients were treated with CS and HXQ All three patients on hemodialysis responded positively to the RTX therapy . Patient HD-1 had Raynaud 's syndrome and finger necrosis ; her symptoms resolved , and she recently received a transplant , 4 years after RTX treatment . Patient HD-2 , who had been on ventilator support with pneumonitis , pleuritis and carditis for 1 month prior to receiving RTX , recovered and has been stable on hemodialysis as an outpatient for > 4 years since RTX therapy . Patient HD-3 , after 3 years on hemodialysis , developed debilitating chorea with increased lupus serology . She did not respond to anti-convulsant therapy . The chorea resolved within weeks of the RTX therapy . She remains on dialysis without recurrence of chorea . B-cell depletion and re-population Figure 1 shows the average B-cell depletion relative to the beginning of the first dose of RTX . Patients received an average of 4.3 ± 1.6 doses overall . B-cell depletion was achieved within 2 weeks of the first dose of RTX and lasted an average of 3 ± 4 months -LRB- range 3 to 12 months -RRB- . Five patients -LRB- 28 % -RRB- received repeated courses of RTX therapy ranging from two to four courses of one to four additional doses following re-population of the B-cell line in the setting of clinical relapse of SLE . Overall follow-up period from the initial dose of RTX to this report was 3.0 ± 1.3 years . It should be noted that those patients who did not have clinical relapse were not routinely assayed for lymphocyte subsets . Therefore , it is not known if or when those patients with persistent clinical remission had their B-lymphocyte lineage re-populated . Fig. 1Graph of B-cell depletion over time from before rituximab therapy to 12 -- 18 months after rituximab therapy . Asterisks indicate significant difference from the post-rituximab values ; P < 0.01 Table 2 describes the changes in the lymphocyte subsets from baseline to the nadir drop in the B-lymphocyte lineage . Total lymphocyte counts , as well as CD4 and CD8 T-cell counts , tended to be lower before RTX treatment and increased after RTX therapy . Similarly , the levels of serum immunoglobulins remained normal in comparison with the pre-RTX values . Table 2Clinical parameters before and after rituximab therapy -LRB- NS not significant -RRB- ParameterBefore rituximab therapyAfter rituximab therapyPTotal lymphocyte count1044 ± 5961734 ± 1535NSCD4 + lymphocytes344 ± 217556 ± 264NSCD19 + lymphocytes243 ± 22374 ± 710.005 Immunoglobulin IgG1603 ± 8481596 ± 1055NSImmunoglobulin IgM273 ± 514283 ± 531NSUpr/cr -LRB- mg/mg -RRB- 4.0 ± 3.50.6 ± 0.60.001 Serum albumin -LRB- g/dl -RRB- 2.6 ± 0.73.5 ± 0.60.001 Scr -LRB- mg/dl -RRB- 1.2 ± 0.40.6 ± 0.20.001 eGFR -LRB- ml/min/1 .73 m2 -RRB- 86 ± 32144 ± 370.0003 Corticosteroid dose -LRB- mg/m2 per day -RRB- 79 ± 2613 ± 20 < 0.0001SLEDAI-2K score47 ± 1925 ± 140.0004 Lupus activity and auto-antibody response Table 2 and Fig. 2 summarize the clinical response to RTX therapy . The average lupus activity score -LRB- SLEDAI -RRB- improved in all patients . Average dsDNA antibody decreased and serum C3 complement increased significantly after RTX therapy . Other serological parameters showed a trend towards improvement as well . Fig. 2Composite graphs depicting response to rituximab therapy on clinical parameters . Panela SLEDAI -LSB- 13 -RSB- scores before and after rituximab therapy . Panelb proteinuria -LRB- Upr/cr -RRB- before and after rituximab . Panelc auto-antibody titers before and after rituximab . Paneld serum complements as C3 and C4 complements . Asterisks indicate significant differences from the post-rituximab values ; P < 0.01 All 15 patients not on dialysis had active lupus nephritis with significant proteinuria . Table 1 provides detailed information regarding the classification of the lupus nephritis for each patient , together with extra-renal manifestations and concurrent or previous therapies , as well as their final outcome . All parameters improved or stabilized in 14/15 -LRB- 93 % -RRB- patients . Seven had total remission of proteinuria , while the other seven had partial remission , with significant improvement in proteinuria and renal function . Coincident with the improvement in renal disease , the requirement for maintenance corticosteroid therapy was reduced in most patients , with an average fall in corticosteroid dosing from 79 ± 29 mg/m2 per day before RTX therapy to 13 ± 20 mg/m2 per day after RTX therapy -LRB- P < 0.0001 -RRB- . Adverse events One patient -LRB- # 7 -RRB- received three doses of RTX shortly after a cycle of intravenous cyclophosphamide -LRB- CYC -RRB- administration in an effort to control lupus serositis and nephritis . She developed Staphylococcus aureus endocarditis , with vegetations on the mitral and aortic valves . She died after open heart surgery . This was considered a death from overwhelming infection most likely related to excessive immune suppression . Her CD4 count prior to RTX was 220/mm3 , possibly related to prior CYC therapy . At the time of her death her serum immunoglobulin levels were normal . Patient # 13 had systemic vasculitis and class IV lupus nephritis . Since she was only 7 years of age , it was decided to treat her with intravenous administration of Solu-Medrol followed by weekly RTX for four doses and concurrent mycophenolate mofetil -LRB- MMF -RRB- as induction therapy . She responded well to RTX , with resolution of her proteinuria and clinical remission of the lupus nephritis . However , she developed symptoms of cerebral vasculitis , with seizures and a cerebral infarct , demonstrated by magnetic resonance imaging -LRB- MRI -RRB- after her fourth dose of RTX . She was treated with intravenously administered gamma globulin -LRB- IVIG -RRB- and two doses of cyclophosphamide . Her neurologic deficits resolved and her vasculitis reversed , as demonstrated by MRI . She remains in remission of the lupus nephritis and cerebritis 6 months after RTX therapy . Mild adverse reactions occurred in approximately half the patients and included pruritis , nausea , or malaise associated with the infusions . These became less when hydrocortisone was added to the pre-medication regimen and the infusion rate was slowed to 6 to 8 hours . Discussion To date , this report has provided the largest long-term experience in children treated with targeted B-cell depletion using the monoclonal antibody , rituximab , for severe SLE . We showed a beneficial effect of the drug in over 90 % of the children in this series , which is consistent with that of previous reports -LSB- 8 , 19 -- 21 -RSB- . Moreover , we were able to demonstrate efficacy in controlling proteinuria in conjunction with a fall in auto-antibodies in those patients with active lupus nephritis , which mirrored that in a series of adult patients -LSB- 19 -RSB- . B-lymphocyte dysregulation is central in the pathogenesis of systemic lupus , with disruption of an individual 's immune homeostasis . These mechanisms are multi-dimensional and are not limited to the single role of B cells in antibody production -LSB- 22 -RSB- . Hence , the elimination of the B-cell lineage , with potential re-population with a `` healthier '' line , is theoretically curative to the patient . The safety of rituximab in young lupus patients remains unanswered . Most of the patients in our cohort tolerated the rituximab well . However , as in the European trial -LSB- 11 -RSB- , our patients were on variable multi-drug regimens . The one patient who died did so from infectious complications in conjunction with severe immune suppression from multiple cytotoxic agents , including both rituximab and cyclophosphamide . Another young patient developed symptoms of cerebral vasculitis , with seizures and encephalopathy . The differential diagnosis included the dreaded progressive multifocal leukoencephalopathy -LRB- PML -RRB- , recently reported to occur in patients treated with rituximab -LSB- 23 -RSB- . Although she showed clinical recovery after cyclophosphamide therapy , the case emphasizes the uncharted risks imposed by the use of drugs without well-studied indications . The efficacy of rituximab may be short-lived in some patients . Resistance to RTX B-cell depletion may be related to antibodies against the human-mouse chimeric protein -LSB- 8 -RSB- . It may also be genetically influenced by polymorphisms of the FcRIIIa gene , responsible for the Fc-γ receptor required for RTX binding to phagocytes -LSB- 24 -RSB- . In our series , all patients had some degree of B-cell depletion after the initial course of RTX . However , five of the 18 patients -LRB- 28 % -RRB- developed clinical relapse in association with re-population of the B-cell lineage . All but one of these responded to additional courses of RTX . This is similar to recent long-term reports in a series of adults -LSB- 25 -RSB- . Treatment regimens in children with SLE do not conform with those of adults developed by carefully designed randomized controlled trials . This may be partially attributable to the fact that children ≤ 16 years of age are excluded from these trials . This has resulted in an ambiguous and often anecdotal approach to pediatric patients , especially those with early onset and severe disease . Although intravenous cyclophosphamide treatment was established as induction therapy for proliferative lupus nephritis over two decades ago -LSB- 26 -RSB- , its short - and long-term toxicity delayed its incorporation into pediatric regimens -LSB- 27 -RSB- . Paradoxically , those with severe disease have received excessive courses of toxic medications in futile efforts to preserve renal function -LSB- 27 -RSB- . More recently , less toxic alternative treatment regimens , including mycophenolate mofetil for both induction and maintenance therapy , have resulted in equal or improved renal survival over conventional therapies -LSB- 18 , 28 -RSB- . Since treatment protocols of children do not conform to conventional protocols for adults , attempts at reporting multicenter experiences are hampered by a lack of consistency in treatment regimens -LSB- 11 , 22 -RSB- . Therefore , anecdotal center experiences such as our own are necessary in developing treatment protocols tailored towards efficacy while decreasing long-term risks on growth , fertility and malignancy . In conclusion , RTX therapy offers a potential innovation in the current treatment regimens for children with aggressive SLE that includes both renal and extra-renal manifestations . The development of a randomized controlled treatment protocol for induction and maintenance therapy in pediatric patients is very much warranted .

B O O O B I I B O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

rituximab
systemic lupus erythematosus
children