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Methotrexate Treatment of Severe Asthma in

ChilIdren

Salomon

Guss, MD,

and

Jay Portnoy,

MD

ABSTRACT.

Seven children from 3

to

14

years

old with

chronic

steroid-dependent

asthma

were

treated with

methotrexate

(MTX).

Asthma in all

of the

patients

had

been

poorly

controlled for

at

least

2

years

despite

the

use

of oral

theophylline

and

inhaled

corticosteroids,

cromo-lyn

and albuterol. All

presented

with

significant

side

effects

as a

result of chronic

systemic

steroid

therapy.

Five

patients

were

atopic

and had been unable

to

tolerate

immunotherapy

because of

systemic

reactions.

Forced

expiratory

volume in

1

second

and

forced

expiratory

flow,

mid-expiratory phase, improved

in

four

patients

after

4 to

6

months of

treatment

with doses

of

MTX

rnigfrom

7.5 to 17.5

mg/wk.

Three

patients

were

able

to

discontinue their

systemic

corticosteroids.

Laboratory

values

including complete

blood cell

count

with

differ-ential and liver enzymes remained

at

baseline in all

except

one

patient,,

who had transient elevation

in

ala-nine aminotransferase and

aspartate

aminotransferase.

One

patient experienced

side effects sufficient

to

require

discontinuation of

MTX. It

is concluded that

MTX

is

effective for

reducing

the need for

systemic

corticoster-oids and for

improving pulmonary

functions

in

some

individuals. The benefits of

MTX

in

this

group of

severe

asthmatics appear

to

justify

the

potential

risks involved

in its

use.

Pediatrics

1992;-89:635-639;-

asthma,

methotrex-ate.

ABBREVIATIONS.

MTX,

methotrexate;

FEVI,

forced

expiratory

volume in 1 second.

Methotrexate

(MTX)

has

recently

been shown

to

be

effective for the

treatment

of

severe

steroid-depend-ent

asthma

in

adults.

13

In

low

doses,

this

drug

has

also been

found

to

be

safe when

given

to

children for

various

inflammatory

diseases such

as

systemic

lupus

erythematosus,

dermatomyositis,

and rheumatic and

psoriatic

arthritis.`7

Its

safety

and

efficacy

in

children

with

severe

asthma

remain

to

be

proven. Since

we

wished

to

reduce the

significant

medication

side

ef-fects and

improve

the

pulmonary

functions of several

children with

severe,

steroid-dependent

asthma,

the

following

open clinical trial

was

performed.

PATIENTS

AND METHODS

Patient Selection

All children

and their

parents

signed

an

informed

consent

form

prior

to

taking

MTX. Patients

were

selected for MTX

treatment

if

they

had asthma

and

were

unable

to

discontinue oral corticosteroids

Fromthe Sectionof

Allergy/Immunology,

TheChildren's

Mercy Hospital,

Kansas

City,

MO.

Received for

publication Jun

10,1991;

accepted Jul

30,1991.

Reprint

requests

to

U.P.)

Sectionof

Allergy/Immunology,

The

Children's

Mercy

Hospital,

Kansas

City,

MO 64108.

PEDIATRICS

(ISSN

0031

4005).

Copyright

©

1992

by

the American Acad-emyof Pediatrics.

despite

aggressive

environmental control and

conventional medical

management.

A

history

of substantial medication-related

toxicity

and poor asthma control

was

sought.

Aggressive

conventional medication schedules included inhaled

corticosteroids

at

doses

of

at

least 800

ug/d

of

beclomethosone,

cromolyn

ata

dose

of

at

least 1 vial

of Intal three times

a

day,

albuterol

ata

dose

of 2 sprays of

a

metered dose inhaler

or

0.5-mL

nebulizer

solution three times

a

day

and

as

needed,

and oral

theophylline

with

blood levels -8

,ug/mL.

Laboratory

studies

performed

prior

to

starting

MTX

included

complete

blood cell count, differential and

platelet

count,

serum

profile including

liver enzymes

(aspartate

aminotransferase,

alanine

aminotransferase,

lactate

dehydrogenase)

and

creatinine,

and

a

urinalysis.

Patients

with

significant

liver

enzyme abnormalities

were not

given

MTX. Pretreatment

liver

biopsies

were not

per-formned.

All

patients

were

advised

to

avoid

sulfa-containing drugs

and

alcohol-containing beverages

and

syrups."'9

Spirometry

and

a

chest

roentgenogram

were

also obtained. Peak

flow

meterswere

given

to

each

patient

with instructions

for

keeping

a

diary,

at

least twice

a

day.

Though

most

patients

had been

keeping

such

diaries

prior

to

initiating

MTX,

the records tended

to

be

incomplete

and

were

generally

not

useful.

Treatment

Methotrexate

was

started

ata

dose

of 2.5

mg/wk.

This

dose

was

increased

by

2.5-mg

increments

every 4 weeks. Once

patients

were

taking

more

than 5

mg/wk,

the

dose

was

given

in

two

doses 1

day

each

week.10

All

patients

were seen at

least

every 4 weeks for

clinical evaluation.

Spirometry

and

laboratory

values

as

well

as

theophylline

concentrations

were

measured with each clinic visit.

After the asthma

was

under control

as

indicated

by

reduced

symp-toms

and increased

peak

flows and

spirometry,

an

attempt

was

made

to

reduce the

patients'

oral

corticosteroid doses. If control

of

the

asthma deteriorated with this

reduction,

the dose

of MTX

was

again

increased.

Morning

cortisol concentrations

were

measured

prior

to

reduc-tion

of corticosteroid doses below

a

physiologic

amount

for all

patients

who

were

able

to

discontinue

systemic

corticosteroids.

Once the

serum

cortisol

was

demonstrated

to

be

physiologic,

oral

corticosteroids

were

discontinued.

Corticotropin

stimulation

tests

have

not

yet

been

performed

on

any of these

patients.

RESULTS

Seven

children

were

treated with MTX

starting

in

November

of 1989. Their initial characteristics

are

shown

in

Table

1.

All

had had

poor control

of their

asthma

for

at

least 2 years and had clinical evidence

of steroid

toxicity

such

as

cushingoid

features and

deceleration of their linear

growth

in

relation

to

their

weight.

11'12

Two

patients (C.W.

and

H.L.)

had

steroid-induced

peptic

ulcer disease and

were

being

treated

with

ranitidine. Five

patients

were

atopic

as

demon-strated

by

skin-prick

tests;

however,

none was

able

to

tolerate

immunotherapy

because

of

frequent

sys-temic reactions

and

worsening

of their asthma.

None

of the

patients

considered

for MTX

therapy

had

ab-normal

liver

enzyme

levels,

so

none were

excluded

for that

reason.

The

duration of MTX

treatment

currently

ranges

from 4

to

17

months.

Prednisone doses

prior

to

initi-PEDIATRICS Vol.

89 No. 4

April

1992

635

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(2)

TABLE 1.

Initial

Description

of

Patients

and

Drug

Doses*

Patient

Age,

Sex

Duration

of

Initial

Pred-

Current

Pred-

Highest

Highest

Allergic Triggers

y

MTX Treat- nisoneDose nisoneDose MTX

Dose,

MTX

Dose,

ment,

mo

mg/wk

mg/kg

S.F.

3 F 9 30

mg

QOD

None

7.5

0.5

None

H.L. 9 F 4

30

mg

QOD

None 12.5 0.4 Mite

C.W. 10 F 17 40

mg

QOD

None 12.5 0.3

Tree, grass, weed

A.B.

13 M 15

60omg

Qday

20Omg

QOD

12.5 0.2 Mite

K.W. 14 M 12 40

mg

Qday

7.5

mg

QOD

17.5 0.4

Grass,

mite

ESB.

14 F 1 30

mg

QOD

30

mg

QOD

2.5

NA Mite

T.M. 11 F 6 40

mg

Qday

40

mg

Qday

17.5 0.2 None

*Abbreviations:

MTX, methotrexate;

QOD,

every other

day; Qday,

once a

day;

NA,

not

applicable.

ation

of

MTX

treatment

ranged

from

30

mg

every

other

day

to

60

mg

daily

as

shown in Table 1. Most

patients

who

experienced

improvement

in

their

asthma

symptoms

noticed this

at

MTX

doses

of

be-tween

7.5

and

10

mg/wk.

One

patient (K.W.)

did

require

12.5

mg/wk

before

he

showed

improvement.

Three

patients (S.F.,

H.L.,

C.W.)

have

now

been able

to

discontinue

their corticosteroids.

Emergency

de-partment

visits

and

hospital

admissions

for

1

year

before

to

1

year after

starting

MTX

are

shown in Table

2.

Though

all

of

these

patients

had

severe

asthma,

their lack

of emergency

department

visits

and

hospi-talizations

suggests

that

their asthma

had been

at

least

somewh-at

controlled

by

their

regimen.

Of the

two

patients (H.L.

and

T.M.)

who did have

large

numbers

of such

visits,

T.M.

did

not

show

improve-ment

with MTX

and

H.L.

was

believed

to

be

noncom-pliant

with

her

medical

therapy.

Linear

growth

and

weight

were

measured

repeat-edly

both

before and after

MTX

therapy

as

shown in

Table

3.

The median

change

in

height

per

weight

was

0.6

cm/kg

before

MTX

and

3.1

cm/kg during

MTX

treatment.

Though change

in

height

was

greater

dur-ing

MTX

treatment

for

only

two

of five

patients (A.B.

and

C.W.),

the

others had

increased

height

in

pro-portion

to

their

weight.

Two

patients (A.B.

and

K.W.)

lost

large

amounts

of

weight during

their 1

year of

MTX

therapy,

reflecting

a

return to

normal

body

proportions.

Spirometry

values

were

obtained

repeatedly

for all

patients

except S.F.,

who

was

too

young

to

perform

a

forced vital

capacity

maneuver

(Fig

1).

All

patients

experienced improved

spirometry

values

except

T.M.

and

E.B.,

who

was

unable

to

take

MTX. In

addition

to

spirometry, patients

were

instructed

to

measure

peak

flows

daily.

One

patient (C.W.)

was

noted

to

have

a

large

amount

of

variability

in

her

peak

flows

which

was

consistently

seen

1

to

2

days

before

each

dose

of

MTX

(Fig 2).

Because

of this

observation,

she

was

switched

to

a

twice-a-week

MTX

regimen

at

the

same

total

weekly

dose

in

an

attempt

to

reduce this

variability.

Her

forced

expiratory

volume

in 1

second

(FEy1)

values

promptly

fell and control of

her asthma

worsened

within 2

weeks,

requiring

a

resumption

of

once-a-week

treatment.

Once

her

asthma

was

again

under

control,

the MTX

dose

was

increased

and

the

weekly variability

resolved. She

was

able

to

discon-tinue

oral

corticosteroids

completely

within the

next

2

months.

Elevated

alanine

aminotransferase

and

aspartate

aminotransferase

developed

in

another

patient (A.B.)

TABLE

2.

Yearly Emergency Department

(ED)

Visits

and

Hos-pital

Admissions

From 1 Year

Before

to1 Year

After

Initiation

of

Methotrexate

(MTX)

Therapy

Patient Pre-MTX

During

MTX

EDvisits

Admissions

ED visits

Admissions

S.F.

0 0 0 1

H.L. 9 3 3 3

C.W.

2 0 2 0

A.B.

0 1 0 0

K.W. 0 1 0 0

E.B. 1 0 0

0

T.M. 6 5 5 5

Mean 2.6 1.4 1.4 1.3

at

a

dose

of

15

mg of

MTX

per week.

This

required

him

to

stop

taking

MTX

until the

enzyme levels

returned

to

normal 2 weeks later.

During

this

time

his

pulmonary

function

tests

worsened

(Fig 3),

neces-sitating resumption

of

high-dose daily

corticosteroids.

Once

the

MTX

was

resumed

at

a

lower dose

(1

2.5

mg/wk),

his

FEV1

improved

and

he

was

again

able

to

tolerate

a

taper

of

his steroid

dose.

Unfortunately,

his

asthma has

not

been

as

well controlled

on

the

lower

dose

of

MTX.

The

youngest

patient

we

treated

(S.F.)

was

2.5

years

old

at

the time that MTX

therapy

was

begun.

Because

she

was

unable

to

use

a

metered dose

inhaler,

her

treatment

consisted

of

a

nebulized

mixture

of

albu-terol,

cromolyn,

atropine (1

mg

three times

a

day),

and

intravenous

methylprednisolone

solution

(20

mg

three times

a

day)

as

well

as

oral

theophylline

and

corticosteroids.

Her MTX

dose

was

gradually

in-creased

to

7.5

mg/wk;

the asthma

symptoms

resolved

and oral corticosteroids

were

discontinued

only

after

she

reached

that

dose.

Subsequently,

she

had

been

able

to

reduce her

MTX

dose

to

2.5

mg/wk

without

recurrence

of

symptoms

or a

need

to

resume

oral

corticosteroids. All

cushingoid

features

have

resolved

and

her

growth

has accelerated. She did

not

experi-ence

any adverse effects from

the MTX.

Two

patients

are no

longer

receiving

MTX.

One

of

them

(H.L.)

discontinued

it

after

4

months

because of

lack

of

compliance

with the

treatment

regimen.

When

she

reached

an

MTX

dose of

7.5

mg/wk,

her

asthma

symptoms

completely

resolved.

The

family

discontin-ued all

of her medications

including

oral

corticoster-oids

and MTX without

seeking

medical advice.

For-tunately,

she

displayed

no

evidence

of adrenal

suppression

despite having

received

long-term

oral

corticosteroid

therapy.

Her

asthma has remained

in

636

METHOTREXATE FOR ASTHMA

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(3)

TABLE 3.

Change

in

Height (Centimeters)

and

Weight

(Kilograms)

From

1

Year

Before

to 1

Year

After

Starting

Methotrexate

(MTX)

Therapy*

Patient

Pre-MTX

During

MTX

AHeight

AWeight

AHt/AWt

AHeight

AWeight

AHt/AWt

S.F.

+9.6

+3.1

3.1

+6.4

+1.5

4.3

H.L.

+6.0

+5.7

1.1

+3.3

+3.6

0.9

C.W.

+5.2

+8.3

0.6

+9.3

+7.3

1.3

A.B.

+2.5

+14.5

0.2

+4.6

-2.8

-1.6

K.W.

+4.5

+9.9

0.4

+3.0

-11.9

-0.2

Mean

±

SD

5.6

±

2.6

8.3

±

4.3

5.3

±

2.6

-0.5

±

7.4

Median

+5.2

+8.3

+4.6

+1.5

*Two

patients

(T.M.

and

E.B.)

werenot

followed

long enough

tomeasure

these

changes.

FVC

100

80

60-

40-100

-80

-60

-40

-Pre

Oni

Mtx

NLx

FeV1

100

-80

-60

-

40-MMEF

p

F

r

Ee

Ed

V

e

d

I

Ir'ev

On

Pre-

On

NLtx

Ilix

Ntx

Mtx

Fig

1.

Percent

predicted

of

spirometry (forced

vital

capacity [FVC];

forced

expiratory

volume

in 1

second

[FEV,];

and

forced

expiratory

flow,

mid-expiratory

phase [MMEF])

of

patients

who received

(Mtx).

One

patient (S.F.)

was

unable

to

perform

an

FVC

maneuver

because

of her young age.

-Sun

Mon Tue Wed Thu Fri Sat Sun Mon Tue Wed

flctato

jutpirt

ahds

fMethotrexate

.

Fiv

. ea

oflourptentsd aoreCW

current

takigrMT.sOn

wely

(K.W.)tio

reustpiore

17. mg/wk

boeofmtotrexawe.cudgau

alyemisinaecete

hiforticostaerbtoid regimn.

Ictoiseno

kneownhowlogths

patients(..

wxeillneed

toacbeptratled

thistreantmentwilal have onfct

wt

teirpulonrystatuods.s

Thve

ou

patients

presurentediyti

review

suffe

fOme

severe

ashma,

which

theye

pallntwl

haeehdsinceinfancy.

All

were

treated

with maximum

conventional

ther-apy.

They

also

required

frequent

bursts

with

systemic

100.

90-80I

70.

60

50

40

30

20

10

0

Mtxstopped

Mtxre-started

.I

1

2

3

4

5

6

1

8

9

10 11 12

13 14

Month

of~Mtx

Fig

3.

Forced

expiratory

volume

in

1 second

(FEVj)

for A.B.

showing

a

dramatic decrease when the methotrexate

(Mtx)

was

discontinued

for

a

short time because

of elevated liver enzymes.

corticosteroids and

eventually

were

unable

to

discon-tinue

them.

Immunotherapy,

which

was

attempted

for

patients

who

were

atopic,

had

to

be

discontinued

because

of

systemic

reactions

and

worsening

of

the

asthma.

These

patients

had

asthma that

was

poorly

controlled,

despite

this

aggressive

treatment.

Some

had

multiple

emergency

department

visits

and

fre-quent

admissions

to

the

hospital.

All

of

these

patients

had

evidence

of

side

effects

due

to

the chronic

use

of

systemic

corticosteroids such

as

increased

body weight, cushingoid

features,

decel-eration

of linear

growth

in

proportion

to

weight,

peptic

ulcer

disease,

mood

swings,

depression,

and

insomnia.

These

patients

were

at

risk

for

development

of

other side

effects

as

well.","2

In

contrast to

the

potentially

severe

and

systemically

global

side

effects

and toxicities of

corticosteroids,

MTX

has

side

effects

that

are more

localized

to

the

liver,

lungs,

gastroin-testinal

tract, and bone

marrow

and

are

therefore

potentially

more

detectable

prior

to

permanent

dam-age.

During

MTX

therapy,

asthma

morbidity

was

sub-stantially

reduced. These

patients

required

fewer

acute

bursts

with

high

doses of corticosteroids.

They

experienced

slightly

fewer

emergency

department

visits

and

admissions

to

the

hospital

and

they

had

a

substantial

improvement

in

their

FEV1

and forced

expiratory

flow,

mid-expiratory phase.

There have been several

reports

involving

adult

asthmatic

patients

who have been shown

to

have

favorable responses

to

MTX.1

'

These

studies describe

patients

who

have

been able

to

tolerate

a

reduction

ARTICLES

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of their

systemic

corticosteroid doses

while

receiving

MTX

and thus have had

a

decrease

in

their

steroid-induced side

effects.

Many

of them

were

able

to

discontinue corticosteroids

completely.

In

a

recent

study,

31

cushingoid

adult asthmatics

were

given

15

to

50

mg/wk

of

MTX

for

18

to

28

months. Prednisone

doses

were

reduced

by

more

than

50%

in

24

of

25

patients

and 15

were

able

to

discontinue their

pred-nisone.

Only

15

of these

patients

reported

transient

side

effects,

which included

nausea,

rash,

thinning

of

hair, stomatitis,

and

transient

elevation

of the

liver

enzymes

in

serum

(aspartate

aminotransferase).

These results

as

well

as

our own

differ from those

recently reported by

Erzurum

et

al114

at

National

Jew-ish

Institute

for

Respiratory

Diseases.

This

difference

may be

partially

due

to

the older

age group treated

in

that

study.

Also,

the

doses of

MTX

were

increased

more

rapidly

than

ours

and the duration

of

treatment

was

much

shorter.

None

of

our

patients

were

im-proved by

3

months and this slow

onset

of

improve-ment

has

been observed

in

all other studies

of

MTX.

It is

also

possible

that

patients

seen

at

National

Jewish

may have

had

a

significant

irreversible

component

in

their

airways

disease. Our

patients

did

have

reversi-bility

as

demonstrated

by

improvement

of their

FEy1.

Adverse

effects from

MTX,

even

in

low

doses,

are

known

and have been

reported

in

children and

adults.10

The

more common

side

effects include

an-orexia,

nausea,

vomiting

and

diarrhea,

and

stomati-tiS.

13

A

pruritic

rash that

usually

appears

6

to

12

hours

after

starting

therapy

is

often caused

by

exposure

to

UV

light.

1

5Mild

elevation

of

serum

liver

enzymes,

which

usually

occurs

during

the

3

days

after

MTX is

taken and

may be

transient,

is

commonly

seen

with

a

low

dose

of

MTX.

This

is

not

necessarily

an

indica-tion

to

discontinue the

drug

if the values

return to

normal

prior

to

the

next

MTX

dose.16-19

One

of

the

patients

in

our

group showed elevation

in

the

serum

liver

enzymes which

returned

to

baseline

levels

after

1

week

off the

drug.

Methotrexate

in

high

doses

has

been

reported

to

cause a

picture

of

pneumonitis,

which is

an

idiosyn-cratic reaction

and

not

dependent

on

the

length

of

treatment.23

Another

reported

side

effect

is

pul-monary

fibrosis.13'

15

Both

of

these

may

cause

an

in-crease

in

the

FEV1-forced

vital

capacity

ratio

and

the

emergence of

an

obstructive-restrictive

pattern

in

the

expiratory-inspiratory spirometry

loop.

It is

not

clear

whether

severely

asthmatic

children with

some

de-gree of irreversible

lung damage

are more

prone

to

develop

2pulmonary

side

effects such

as

pulmonary

fibrosis.

A

rare

complication

is

liver

fibrosis and

cirrhosis,

which is

usually

nonprogressive

after the

drug

has

been

stopped.

192'0

This

has been

primarily

observed

with

high

dose of

MTX.

Because

of

this,

a

few

centers

perform

liver

biopsies

as

part

of their

routine

follow-Up.21

This

side

effect

is

very

rare

with

low doses of

MTX

and

usually

affects

patients

with

preexisting

liver

problems

such

as

extremely

obese

patients,

chronic

alcoholics,

and

diabetic

patients.2

Bone

mar-row

suppression

is

rare

in

low-dose

MTX,25

as

is

generalized

vasculitis

with

fever.15'25

MTX is

known

to

be

teratogenic

when taken

early

in

pregnancy.

Reversible

oligospermia

has also been

reported.

26

At

the

present,

MTX is

used

to treat

children with

two

different groups of diseases:

malignancy

and

various

inflammatory collagen

vascular

diseases.

For

the

treatment

of

malignant

2disorders,

doses

of

50

to

150

mg/wk

are

often

used.27

These

doses

are

associ-ated

with

frequent

side

effects.28

Lower

doses such

as

5

to

25

mg/wk

are

used for

the

treatment

of

rheu-matoid

arthritis,

psoriatic

arthritis,

systemic

lupus,

and

polymyositis/dermatomyositis.

These doses

are

believed

to

be

safe and

usually

are

associated

with

only

minor

side

effects.`7

The mechanism

by

which

MTX

affects the asthma

is

not

completely

understood.

It

may be due

to

the

fact

that MTX in low

doses

is

an

anti-inflammatory

drug

that

suppresses

the

small

aiirwa

inflammation

that

is part

of

the asthma pahlgy

L30

The

drugi

a

folic acid

analogue

with

a

variable

half-life that

is

50% bound

to

albumin.'10'31

It is

primarily

excreted

in

the urine via

glomerular

filtration and

active

proximal

tubular

secretion.3

Methotrexate

does

have

a

reduced

clearance

in

renal disease which

requires

a

dose

ad-justment.

The

MTX

dose

required

to

suppress

inflam-mation

is

lower

than

the

immunosuppressive

dose.333

Low

doses

of

the

drug

inhibit both

neutro-phile

chemotaxis and wheal and

flare

responses.354

Recently

it

was

found

to

suppress

the LTB-4

genera-tion in

neutrophils

by

inhibition

of

5-lipoxy~-.enase

and leukotriene

A4

epoxide hydrolase

activity.

1

Low

doses

of

MTX

also inhibit the

primary

and

secondary

antibody

response.

42

Several

drugs

have

been

reported

to

interact

with

MTX. Its

displacement

from

albumin has

been

re-ported

with

barbiturates,

salicylates,

sulfonamide,

tet-racycline, probenecid,

and

phenytoin.3

its

renal

se-cretion

may

be inhibited

by

salicylates, penicillins,

probenecid,

and

sulfonamide.31

Some

drugs-eg,

penicillins,

folic

acid,

cephalothin,

and

corticoster-oids-might

interfere

with its

cellular

uptake,

which

might

be crucial

in

children.8

Bone

marrow

suppres-sion

may be

potentiated

by sulfa-containing drugs.

We

did

measure

theophylline

concentrations

repeat-edly

and,

in

accordance

with the

literature,

they

were

not

affected

by

MTX.

This

was an

open and uncontrolled trial of

MTX

for

treatment

of

severe

asthma in

children.

For

this

reason,

we

cannot

make the

general

statement

that

populations

of asthmatics similar

to

our own

will

respond

differently

to

MTX

than

to

placebo.

We

can

state

that

several of

our

patients

experienced

a

clear

and

unequivocal

response

to

MTX

that

reversed when

the

drug

was

discontinued

and recurred when

it

was

restarted.

The

nature

of

statistical

inference

is

such that

sig-nificant differences between

populations

cannot

be

applied directly

to

individual

patients.

For

this

pur-pose, open

trials such

as

the

current

one can

provide

guidance

to

practitioners

who may

wish

to

provide

this

type

of

treatment

on a

trial basis.

A

patient

either

will

respond

or

will

not

respond.

We

suggest

that

it

is

reasonable

to

try

MTX

when

patients

fail

to

respond

to

conventional

treatment

and

are

at

risk

of

substan-tial

toxicity.

This

toxicity

can

be

both

physical

(from

638

METHOTREXATE FOR ASTHMA

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(5)

side

effects of

medications)

and

psychologic

(from

having

to

follow

extremely

difficult medication

regi-mens).

The question

of

patient

compliance is always

of

great importance.

Since

MTX is given on a

once-a-week schedule,

it

has

an

obvious advantage

in

this

respect.

We would therefore ask whether MTX should

be used

in

severe

asthmatics who

are

noncompliant.

The

answer to

this

question

would be

particularly

germane

for the so-called

fatality-prone

asthmatics.

It is

possible that the risk of

asthma

death could

be

greater

than

the

risk of adverse

effects from

MTX. At

this point, there

are

simply

no

data

available

to

justify

its use in

this situation,

but

we

do

suggest

that clinical

trials be

performed

to answer

this

and other questions

pertaining

to

MTX treatment

of asthma.

CONCLUSION

Methotrexate

as an

anti-inflammatory,

immune-modulating

agent

has

proven to

be

effective for

the

treatment

of several

severe

steroid-dependent

asth-matic

children.

It

permitted

them to

decrease their

use

of

systemic

corticosteroids and resulted

in

a

de-crease in

steroid-related side

effects.

Few

signs

of

MTX-related

toxicity were

found

at

doses of

up to

17.5

mg/wk.

Asthma

symptoms

improved

in

most

of

our

patients and

three

were

able

to

discontinue their

corticosteroids completely. Additional clinical

trials

of

this

drug

appear

warranted

to

determine

its

long-term

effects

on

asthmatic

children,

which patients

will

benefit from

it, and

its

indications.

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treatment in corticosteroid-dependent asthma. Ann Intern Med. 1990;112:577-581

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3. ShinerRJ,NunnAJ,ChungKF, Geddes DM. Randomized, double-blind, placebo-controlledtrialof methotrexateinsteroid-dependent asthma. Lancet.1990;336:137-140

4. Rose CD, Singsen BH, Eichenfield AH, Goldsmith DP, Athreya BM. Safetyandefficacy ofmethotrexate therapy for juvenile rheumatoid arthritis.IPediatr. 1990;117:653-659

5. Wallace CA,BleyerWA,SherryDD, Salmonson KL,WedgewoodRJ. Toxicity and serum level of methotrexate inchildren with juvenile rheumatoid arthritis. Arthritis Rheum. 1989;32:677-681

6. Hollingsworth P, CraftA,AnsellBM.Low-dose methotrexateinsystemic

onsetjuvenilechronic arthritis.ClinExpRheumatol.1989;7:647-650 7. Rodriquez-NunezA, Femandez B,RodriguezE,etal.Polymyositisand

dermatomyositisinchildhood.AnEsp Pediatr. 1988;29:288-292 8. Evans WE, Christensen ML. Drug interactions with methotrexate. J

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trimethoprim-sulfamethoxazole. I

Rheumatol.1986;13:440-441 10. ChristophidisN. Methotrexate.Clin Rheum Dis.1984;10:401-415 11. Axelrod L. Glucosteroidtherapy.Medicine(Baltimore).1976;55:39-65

12. Schleimer RP. Glucocorticosteroids: their mechanism of action and use

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13. WeinblattME.Toxicity of low-dose methotrexateinrheumatoid arthritis. I Rheumatol.1985;12(suppl12):35-39

14. ErzurumSC, LeffJA, Cochran JE,etal.Lack of benefit of methotrexate insevere,steroid-dependentasthma: adouble-blind, placebo-controlled study.Ann InternMed.1991;114:353-360

15. KaslowJE, MoveyMS. Methotrexateusefor asthma:acriticalappraisal. AnnAllergy. 1989;62:541-545

16. Tugwell P, Bennet K, Geret M. Methotrexate in rheumatoid arthritis: indications, contraindications and safety. Ann Intern Med. 1987;107:358-366

17. Reynolds FS, Lee WM. Hepatotoxicity after long-term methotrexate therapy. South MedJ. 1986;79:536-539

18. Warin AP, Landells JW, Levene GM, et al. A prospective study of the effects of weekly oral methotrexate on liver biopsy. BrI Dermatol. 1975;93:321-327

19. Lanse SB,Arnold GL, Gowans JDC, Kaplan MM. Low incidence of hepatotoxicity associated with long-term, low-dose oral methotrexate in

treatment of refractory psoriasis, psoriatic arthritis, and rheumatoid arthritis:anacceptablerisk/benefitratio.Dig Dis Sci. 1985;30:104-109 20. Cannon GW, WardJR,Clegg DO, Samuelson, COJr,Abbott TM. Acute

lung disease associated with low-dose pulse methotrexate therapy in patients withrheumatoid arthritis. Arthritis Rheum. 1983;26:1269-1274 21. Carson CW, Canno GW, EggerMJ,etal. Pulmonary disease during the

treatmentof rheumatoid arthritis with low-dose pulse methotrexate. Semin Arthritis Rheum. 1987;16:186-195

22. Sootman HD, Matthay RA, Putman CE, et al. Methotrexate induced pneumonitis.Medicine(Baltimore). 1976;55:371-388

23. Engelbrecht JA, Calhoon SL, ScherrerJJ. Methotrexate penumonitis after low-dose therapy for rheumatoid arthritis. Arthritis Rheum. 1983;26:1275-1278

24. Bell MJ, Geddie WR,Gordon DA, et al. Pre-existing lung disease in patientswith rheumatoid arthritis (RA) maypredispose to methotrexate (MTX)lung. Arthritis Rheum. 1986;29(suppl):575

25. Zachariae M. Methotrexateside-effects. BrIDermatol. 1990;122(suppl 36):127-133

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27. Kastrup EK. FactsandComparisons. St Louis, MO: JB Lippincott Com-pany;1981:653-654

28. Winkelstein A. Immune suppression resultingfrom various cytotoxic agents: immune suppressionand modulation. In: MitchellMS,Fahey JL,eds. Clinics in Immunology and Allergy. Philadelphia, PA: WB Saun-ders;1984;4:295-315

29. Hersh EM, Wong VG, FreireichEJ.Inhibitionof the local inflammatory responseinmanby antimetabolites. Blood. 1966;27:38-48

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31. Huffman DH,WanSH,AzarnoffDC, et al. Pharmacokineticsof

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32. Liegler DG, Henderson ES, Hahn MA, et al. The effect of organicacids

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33. Hurd ER. Immunosuppressive andanti-inflammatory properties of cy-closophamide, asathioprine and methotrexate. Arthritis Rheum. 1973;16:84-88

34. OlsenNJ, Callahan LF,Pincus T. Immunologic studies of rheumatoid arthritis patients treated with methotrexate. Arthritis Rheum. 1987;30:481-488

35. CreamJJ, Pole DS. The effect of methotrexate and hydroxyurea on neutrophilchemotaxis.BrIDermatol.1980;102:557-563

36. SuarezCR, Pickett WC, Duncan HB, McClintock DK, Oronsby AL, KerwarSS. Effect of low dose methotrexateonneutrophilchemotaxis induced by leukotriene B4 and complement C5a. I Rheumatol. 1987;14:9-11

37. O'CallahanP, ForrestMJ,BrooksPM.Inhibition ofneutrophil

chemo-taxis inmethotrexatetreated rheumatoid arthritis patients. Rheumatol Int.1988;8:41-45

38. JohnsonCA,Russell

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Kovithavongs T, Dasgupta M.Measurementof immunologic and inflammatory responsesinvitro inrheumatoid

arthri-tispatientstreated with methotrexate.IRheumatol.1986;13:294-296 39. Ternowitz,Bjerring P,Andersen PH, Shcoder JM, Kragballe K.

Metho-trexateinhibits the human C5a-induced skin responseinpatients with psoriasis.IInvestDermatol.1987;89:192-196

40. Vande Kerkoh CM, Bauer FW, Maasoen-de Grood RM. Methotrexate inhibits the leukotriene by induced intraepidermal accumulation of polymorphonuclear leucocytes.BrJDermatol.1985;113:251a-255a

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Methotrexate Treatment of Severe Asthma in Children

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