Effectiveness Azathioprine

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No systematic review and no RCTs inform us about the use of azathioprine. Its use is confined to certain specialists and, anecdotally, it appears to have limited efficacy. An ongoing RCT has been identified on the Cochrane Skin Group's ongoing clinical trials register (see http://www.nottingham.ac.uk/~muzd) which is due to report in late 2002.

Systemic steroids

Systemic prednisolone is commonly used in short bursts (a few weeks) for severe atopic eczema. The systematic review concluded that the potency of this approach beyond that of placebo was large (Table 17.8).2,4,10 There are no trials that properly evaluate the treatment according to Helsinki protocols (i.e. against another validated form of immunosupression such as ciclosporin). The trials also did not report long-term relapse rates or follow up disease severity.

Ciclosporin

The systematic review found ciclosporin to be effective, although of unknown efficacy compared with systemic steroids. Of the 10 available trails,1,3,11,14-18,20,21 three studies11,15,18 were systematically pooled with respect to itch scores. The pooled mean difference in itch scores was 15 (95% CI 9 to 23) points lower for ciclosporin, as assessed by a self-reported visual analogue scale (up to 100 mm).

The degree of stress, brought upon physician and patient alike by the use of this drug with potentially serious side-effects,19 is almost certainly significant and might reasonably be expected to impact upon quality-of-life scores. This omission in the studies and lack of comparison with the "best of the rest" of the immunosuppressive agents makes it difficult to know if ciclosporin can be recommended in preference to systemic steroids.

Phototherapy and photochemotherapy

Broadly speaking, light therapy appears to improve responses in patients, and these responses are extremely significant if the placebo effect is included (tanning makes placebo effect dissociations near impossible). The extent to which the disease is improved by the physiological response of tanning compared to the psychological effect of being tanned is a fundamental problem. The systematic review identified six RCTs5-9,12 and we identified a further one13 (Table 17.9). The seven trials differed in methodology, with randomisation, blinding and controls proving difficult. Most of the trials suggest positive results.

Drawbacks

All of the immunosuppressants currently available carry potentially serious side-effects such as kidney damage (ciclosporin), bone marrow suppression (azathioprine), osteoporosis (systemic steroids) and skin cancer (photochemotherapy). These are described in more detail in the systematic review. It is difficult to make any statements about how useful these drugs are in comparison with one another because the impact of these adverse effects (for example azathioprine-induced bone marrow

Study

Interventions and comparator

Study population and sample size

Trial design, description and follow up

Outcome measures

Main reported results

Quality of reporting

Comment

Dickey 19762"* (USA)

Betamethasone 22 patients with sodium phosphate moderate-to-severe

4-0 mg/ml Injection v atopic dermatitis dexamethasone sodium phosphate

4-0 mg/ml injection once daily

Oral plus nasal beclomethasone dlpropionate three times daily v placebo

27 children with moderate-to-severe atopic eczema

Systemic flunlsollde 640-1200 micrograms twice daily v placebo

20 children with severe atopic dermatitis

Prospective, randomised, parallel study; 24 hours duration

Prospective, randomised, crossover study; 4 weeks duration

Inflammation, veslculatlon, pruritus, exudation, excoriations, overall evaluation

Patient-assessed itch and sleep loss (VAS); physician-assessed redness, veslculatlon, crusting, excoriation, llchenifl cation

Prospective, randomised, crossover study; 2 weeks duration

Pruritus, erythema/oedema, excoriation, papulatlon/erosion/ scaling, lichenlficatlon

Overall evaluation on a four-point rating scale: with betamethasone, 3-44 (baseline) reduced to 2-89; with dexamethasone 3-62 (baseline) reduced to 2-69

Only parental score for Itch and antihistamine use were significantly lower on beclomethasone than on placebo; use of topical steroids and sleep loss did not show any significant change; other significant changes, particularly surface damage

Improvement over baseline for total clinical severity score: group A, 75 reduced to 34; group B, 74 reduced to 29

Method and concealment of randomisation unclear; study described as double-blind; withdrawals and dropouts not mentioned

Method and concealment of randomisation unclear; study described as double-blind; 1 withdrawal, no ITT

Although a placebo group might have been ethically difficult, patient-based views on treatment response would have been useful

Crossover study with significant treatment order interactions; large treatment effects

Method and concealment of randomisation unclear; study described as double-blind; withdrawals/dropouts not mentioned

Big treatment effects

"used physician-assessed global severity ♦used patient-assessed global severity

Table 17.9

Randomised controlled trials of phototherapy and photochemotherapy in atopic dermatitis

Study

Interventions

Study

Trial design,

Outcome

Main reported

Quality of

Comment

and comparator

population and

description

measures

results

reporting

(co-treatments)

sample size

and follow up

Reynolds

Twice-weekly TLO-1

73 patients; 16-65

Prospective,

Patient-assessed Itch

UVB reduced disease

Structured ITT

13 dropouts had to be

et al. 200113

NBUVB

years old

controlled

scales, area scores

score by 6-7 points (95%

analysis and

included; advantage of

(UK)

(150 mJ/cm2) 1/

randomised study

and physician

CI 2 to 12) over visible

adequately attempted

UVA over UVB; not

UVA 15 J/cm2 for

with follow up

assessed 6-slte score

light. UVA reduced the

blinding

significant despite

12 weeks or visible

3 months after

summation for

same by 1 points (95%

conclusion

fluorescent light

last dose

disease activity

CI - 5 to 3).

Jekler and

Three-times-weekly

17 patients over 15

Prospective,

Patients assessed for

Improvement from

Described as

Unclear if randomisation

Larko, 19886

UVB (20-153 mJ/cm2

years of age, most

randomised,

pruritus, lichenlfi-

baseline of 1-5 (mean) to

randomised but

referred to side of active/

Study 1

up to 63-816

of whom had skin

controlled

cation, scaling,

0-7 for UVB and 1-4 for

method unclear;

placebo treatment or to

(Swe)

mJ/cm2) v placebo

type III (tans easily,

left-right parallel

xerosis, veslculatlon,

placebo for overall

blinding unlikely

type of MED; large

(visible light), three

seldom burns)

study of

excoriations,

clinical response

because of mild

treatment effect for all

times

8 weeks duration

erythema; variables

(P<0-001) Thus the total

burning on UVB-

parameters; many dropouts

per week

assessed on a scale

score was significantly

treated side; no ITT

(11/17) because of

(emollients and

of 0-3, plus a global

lower for the UVB-treated

analysis

"Intercurrent disease" and

hydrocortisone)

assessment

side

lack of time for treatments

Jekler &

Three-times-weekly

25 patients, mean

Randomised

As for Study 1 above

Clearing or considerable

Methods very scanty;

Further details of study

Larko, 19886

UVB given at 80%

age 25-9 years,

right/left side

Improvement In 15/25 on

randomisation

found In Jeckler 1992

Study 2

MED versus UVB at

most with skin

parallel study for 8

high-dose UVB 1/16/25

unclear; probably

thesis. This study of high-

(Swe)

40% of MED

type III

weeks

with low-dose (not

unblinded; no ITT

v low-dose UVB sugg

(emollients and

statistically significant)

analysis

ested very little difference

hydrocortisone)

between the two, but

power of study Is very

limited

Jekler and

UVA (average 8-1

33 patients, mean

Prospective,

Patients assessed

Improvement from mean

Described as single

Both treatments Induced

Larko, 19917

mW/cm2) 1/ UVB

age 23-3 years;

randomised left

for pruritus,

baseline of 10-3 (range

blind and randomised

large improvements

(0-85 mW/cm2)

mean disease

right parallel study

lichenlficatlon, scaling,

6-18) for clinical sign

but methods unclear;

compared with baseline,

Study

Interventions and

Study

Trial design,

Outcome

Main reported

Quality of

Comment

comparator

population and

description

measures

results

reporting

(co-treatments)

sample size

and follow up

(Swe)

Three-tlmes-weekly

duration of 19-6

of 8 weeks

xerosis, veslculatlon,

(total score) decreased to

differential tan on UVA

with some small

(emollients and

years; most with skin

duration

excoriations,

5-5 for UVA and 6-4 for

side of the body likely

statistically significant

hydrocortisone)

type III

erythema and an

UVB. Pruritus scored

to have unbllnded

change In favour of UVA.

overall evaluation on

separately with baseline

study; 12 withdrawals

Most patients preferred

a score of 0-3 (none

of 2-2, Improving to 1-1

and dropouts, no

UVA

to severe); healing

after UVA and 1 -3 after

description given; no

evaluated on a scale

UVB.

ITT analysis

of 3 to -1 (3 = healed,

-1 = worse)

Jekler 19925

Mixed UVA (74%)

30 patients, mean

Prospective,

Patients assessed for

A decrease from baseline

Described as

This thesis also presents

(Swe)

and UVB (26%) 1/

age 24-8 years;

randomised

pruritus, lichenlfi-

score of 10-8 to 5-2 for

randomised but

the two studies reported

UVB Three-times per

mean disease

left-right parallel

cation, scaling,

UVA/B and 6-1 for UVB

method unclear; no

In Jekler and Larko, 19886

week

duration 20-5 years

study of 8 weeks

xerosis, veslculatlon,

(P = 0-002 for difference

blinding; no

In more detail; a further

duration

excoriations, erythe

In scores between

withdrawals or

three small left-right

ma and an overall

treatments); 21/24

dropouts

comparison studies are

evaluation on a score

patients reported mild

also described comparing

of 0-3 (none to

burning with UVB (severe

UVA 1/ UVB, low-dose

severe); healing

In 6 patients) compared

UVB 1/UVA/B, and UVA

evaluated on a scale

with 3 episodes of mild

1/ UVA/B, but it Is unclear

of 3 to -1 (3 = healed,

burning with UVA/B (none

If these were RCTs

-1 = worse)

severe)

Krutmann

High-dose UVA1

25 young adults with

Prospective,

Costa scoring

A decrease from baseline

Described as

Unclear If patients

et ai. 19923

(0-130 J/cm2 once

atopic eczema and

randomised,

system: erythema,

of 53 (overall score) to 14

"randomly selected

randomised but confirmed

(Ger)

dally) i/UVA/B

definite atopy

parallel study of

oedema, vesicles,

after UVA1 (P<0-001

patients" but method

by authors; large

therapy (up to 30

15 days duration

exudation, crusts,

against comparator

unclear; ( personal

treatment effects, all in

J/cm2 UVB and 7.5

excoriations, scales,

change); comparative

communication)

favour of high-dose UVA

Study

Interventions and

Study

Trial design,

Outcome

Main reported

Quality of

Comment

comparator

population and

description

measures

results

reporting

(co-treatments)

sample size

and follow up

J/cm2 UVA dally

licheniflcatlon,

data for UVA/B not given

"treatments randomly

over UVA/B

(emollients)

pruritus, loss of sleep

but shown In graphical

allocated"; no

on a seven-point

form only; baseline score

blinding; no dropouts

scale (0 = no lesion,

of 52 decreased to 38

or withdrawals

6 = extremely severe)

with UVA/B (estimated

from graph)

Krutmann

High-dose UVA

53 patients with

Prospective,

Costa scoring

Improvement over

"A randomisation

Very short duration;

et al. 19983

130 J/cm2 once dally

acute severe

randomised,

system: erythema,

baseline for total clinical

sequence generated

results had to be

(Ger)

1/once-daily

exacerbation of

parallel study of

oedema, vesicles,

score: high-dose UVA1

by random numbers";

estimated from graphs;

fluocortolone 0-5%

atopic eczema

10 days duration

exudation, crusts,

baseline of 56 reduced to

no blinding; no

useful to have a

cream or ointment v

excoriations, scales,

26; fluocortolone baseline

withdrawals or

comparison with topical

UVA/B MED once

licheniflcatlon,

of 60 reduced to 35; UVA/B

dropouts

steroids; study suggests

dally

pruritus, loss of sleep

baseline of 60 reduced to

superiority of high-dose

on a seven-point

42 (all after 10 days'

UVA over a topical steroid

scale (0 = no lesion,

treatment) P<0-0001.

6 = extremely severe)

Mean reduction In total

disease activity was 9-7

for 21 évaluable patients

on NBUVB, 4-8 on UVA

and 0-4 on placebo, the

change significant at the

5% level (P<0-05) for

Reynolds

NBUVB v placebo only

et al. 199912

NBUVB (up to 1-2

73 adult patients with

Prospective,

Five clinical features

Proportion of patients

Study described as

Published In abstract form

(UK)

J/cm2) 1/ UVA (up to

moderate-to-severe

randomised,

at 6 separate body

reporting reduction In Itch

randomised (In

only at time of report; only

15 J/cm2) or placebo

atopic eczema

double-blind

sites plus Itch and

over 24 treatments was

balanced blocks),

47 out of 73 patients

Study

Interventions,

Study

Trial design

Outcome

Main reported

Quality of

Comment

co-treatments

population and

description

measures

results

reporting

sample size

and follow up

(visible light) all

parallel study of

sleep loss (VAS),

90% (P= 0-02) for

controlled, and double

completed the study;

twice weekly (mild-to-

12 weeks duration

and extent of disease

NBUVB, 63% for UVA

blind; no ITT analysis

study possibly partly

moderate topical

recorded by one

and 53% for placebo

unblinded because of

steroids plus

observer

(P= 0-02 compared with

lack of pigmentary

emollients)

placebo); changes for

changes on one side and

sleep loss failed to reach

burning on other

statistical significance

Der-

NBUVB 1/ bath PUVA

12 patients with

Prospective,

Patient-rated Itch and

Baseline scores of 100%

Study described as

A small study which took

Petrosslan

1 mg/l as

severe/chronic

randomised,

sleep loss (VAS 0-10

SCORAD for bath-PUVA

randomised, and

care to ensure that both

et al. 200022

8-MOP three times

atopic dermatitis,

single-blind half-

cm) as part of

and UVB reduced by

Investigator blinded;

treatments were given In

(Austria)

per week

age 27 ± 11 -3 years

side comparison;

SCORAD, doctor-

65-7% for bath-PUVA

no ITT analysis; two

equal doses; big falls In

(mean ± SD)

6 weeks duration

rated global severity

treated side and 64-1%

withdrawals, one due

SCORAD scores for

and global changes

for UVB treated side

to exacerbation of

both treatments with little

of modified SCORAD

(P=0-48)

atopic dermatitis, one

difference between

for eight signs and

because of fewer

the two

symptoms

erythema reactions to

the bath-PUVA side

CI, confidence Intervals; NBUVB, narrow-band UVB; MED, minimal erythema dose (I.e. minimal dose to produce redness); 8-MOP, 8-methoxypsoralen; SCORAD, severity scoring of atopic dermatitis VAS, visual analogue scale toxicity) can be predicted by tests beforehand and others (for example kidney damage with ciclosporine) can be identified at an early stage before any permanent damage has occurred. The relative efficacies of systemic immunosuppressants are therefore contingent upon the way they are used.

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